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N - C > Applied Neuropharmacology > Flashcards

Applied Neuropharmacology Flashcards

1
Q

Describe the sequence of events in synaptic transmission.

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

What receptor types are there in neurotransmitters?

A

Usually multiple receptor-types (both ionotropic and metabotropic) for each neurotransmitter

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3
Q

What is the difference between the synaptic transmission of ACh and most other transmitters?

A

ACh is inactivated by enzymatic breakdown in the synaptic cleft

Most other neurotransmitters are inactivated by high affinity uptake unto neurones and glia

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4
Q

How would blocking voltage gated Na channels effect synaptic transmission?

A

Reduce synaptic transmission

e.g. local anaesthetic
Blocks all action potentials so isn’t too useful

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5
Q

How would blocking voltage gated Ca channels effect synaptic transmission?

A

Reduce synaptic transmission

e.g. Those clever spider toxins
Would block all transmitter release, not too useful

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6
Q

How would blocking the release machinery effect synaptic transmission?

A

Reduce synaptic transmission

e.g. Botox
Would block all transmitter release, not too useful

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7
Q

How would blocking the postsynaptic receptors effect synaptic transmission?

A

Reduce synaptic transmission

e.g. Receptor antagonists
Competitive or non-competitive
(Selectivity helps)

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8
Q

How would increasing the breakdown of transmitter effect synaptic transmission?

A

Reduce synaptic transmission

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9
Q

How would increasing the uptake of transmitter effect synaptic transmission?

A

Reduce synaptic transmission

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10
Q

How would inhibiting synthesis and packaging of transmitter effect synaptic transmission?

A

Reduce synaptic transmission

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11
Q

Why is using an agonist to activate the postsynaptic receptors not so useful?
What is a better alternative?

A

Using an agonist to activate the postsynaptic receptors isn’t so useful because they get activated all the time (most of which is inappropriate)

Better to use an allosteric drug that doesn’t activate the receptor on its own, but potentiates the effects of the endogenous transmitter
e.g. benzodiazepines and barbiturates on GABA receptors

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12
Q

How would blocking the breakdown of transmitter effect synaptic transmission?

A

Increase synaptic transmission

e.g. anticholinesterases on ACh

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13
Q

Why is it hard to design drugs to specifically target effects of a synaptic transmission?

A

Most drugs are “dirty” drugs.
Wont just do one thing and will effect many different areas.

There is a limited range of neurotransmitters.

  • So it should be no surprise that a single neurotransmitter has multiple functions in different regions
  • Often in the brain and in the peripheral nervous system (separated by blood brain barrier)
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14
Q

What is the limited range of neurotransmitters?

A 
Acetycholine
Monoamines
Amino Acids
Purines
Neuropeptides
NO
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15
Q

List the Monoamine neurotransmitters

A

Noradrenaline
Dopamine
Serotonin (5-HT)

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16
Q

Name the Amino Acid neurotransmitters

A

Glutamate
GABA
Glycine

17
Q

Name the Purine neurotransmitters

A

ATP

Adenosine

18
Q

Name the Neuropeptide neurotransmitters

A

Endorphins
CCK
Substance P

19
Q

Why is NO a unique neurotransmitter?

A

NO isn’t packed up and released on Ca dependent exocytosis.

It is produced on demand as it is lipid soluble

20
Q

Each neurotransmitter has 3 different attributes what are they?

A

Its own anatomical distribution

Its own range of receptors it acts on

Its own range of functions in different regions (some separated by the blood brain barrier)

21
Q

Dopamine effects what physiological functions?

A

Vomiting
Voluntary movement
Emotions

22
Q

What is Parkinson’s disease?

A

Degeneration of Dopamine cells in the substantia nigra (nigrotriatal)

This causes a dopamine deficiency in the basal ganglia

Symptoms and signs:

  • Tremour, Slowness, Stiffness, Stooped over posture
  • Get gradually worse over time
23
Q

What is the key enzyme in Dopamine synthesis which is lost in Parkinson’s disease?

A

Tyrosine Hydroxylase
(converts tyrosine to DOPA)

Enzyme that converts DOPA to dopamine will still be abundant.
If you can get DOPA in you will get Dopamine produced

24
Q

Explain the difference in DA synthesis between the periphery and brain and the pharmacological significance of this

A

Tyrosine cannot be converted to DOPA in the brain

Tyrosine can be converted to Dopamine in the periphery

Dopamine cannot cross blood brain barrier but tyrosine and dopa can.

Dopa could be given but this would greatly increase peripheral Dopamine therefore enzyme for converting DOPA to dopamine is pharmacologically blocked

25
Q

Explain dopamine receptors

A

No ionotropic receptors (so dopamine cannot evoke fast EPSPs or IPSPs)

5 subtypes of metabotropic (i.e. g-protein coupled) receptor named D1-D5

Dopamine can produce many effects, and different effects in different brain regions, depending on which receptors are expressed

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

26
Q

How is dopamine broken down?

A

2 pathways (both breaking dopamine down to homovanillic acid)

MAO-B and COMT are the key enzymes in dopamine breakdown

27
Q

List the dopaminergic drugs

A

DA precursor
-Levodopa (most effective)

DA agonists

  • Bromocriptine, pergolide (considered old fashioned)
  • Ropinirole
  • Pramipexole
  • Apomorphine

These drugs improve the symptoms of PD

28
Q

What enzyme inhibitors can you use to treat PD?

A

Peripheral AAAD inhibitors
-Carbidopa, benserazide

MAOB inhibitors
-Selegiline
COMT inhibitors
-Entacapone

These drugs have no effect on synthetic dopamine agonists

29
Q

What do enzyme inhibitors add to the treatment of PD?

A

Peripheral AAAD inhibitors
-Reduces peripheral side effects of levodopa and allows a greater proportion of the oral dose to reach the CNS

Dopamine enzyme inhibitors
-Reduce the metabolism of dopamine and so increase the effectiveness of levodopa

30
Q

Dopaminergic drugs have what effects?

A

Improve Parkinson’s
-e.g. rigidity and bradykinesia in the limbs

Worsen or cause

  • Nausea
  • Vomiting
  • Psychosis

Fail to help:

  • Midline features
  • e.g. dysathria, balance, cognition
31
Q

What is dysathria?

A

Slurred speech

32
Q

What effects will dopamine antagonists have?

A

Improve:

  • Nausea
  • Vomiting
  • Psychosis

Worsen or cause:

  • Parkonsin’s/ parkinsonism
  • e.g. rigidity and bradykinesia in the limbs
33
Q

Discuss vomiting and the blood brain barrier

A

Dopamine antagonist antiemetics will worsen PD and generally should not be used in people with PD.

Area postrema (vomiting centre) in the medulla is functionally OUTSIDE BBB.

if there was a DA antagonist that didn’t cross the BBB that would be ok
(There is: DOMPERIDONE)

34
Q

Describe domperidone

A 
DA antagonist
Anti-emetic
Does not cross the BBB
No antipsychotic properties
Relatively safe to use in PD
Has permitted the therapeutic use of apomorphine (which is a powerful emetic)
35
Q

Treatments may cause dyskinesia.
What is dyskinesia?
What may cause it?

A

Abnormal involuntary movements = AIMs

Dopaminergic drugs
-May cause dyskinesia
(e.g. chorea)
“too much movement”

DA antagonists
-May cause parkinsonism
“not enough movement”

36
Q

What may happen with long term DA antagonist use?

What do you do about it?

A

Anti-emetics? NO
-Chronic vomiting doesn’t happen

Antipsychotics? Yes
-Often no alternative

Often cause parkinsonism
-e.g. receptor blockade in basal ganglia

Sometimes cause dyskinesias:

  • Tardive dyskinesias (orofaciolingual)
  • —Hard to explain: up regulation or increased sensitivity of certain DA receptors
37
Q

What drugs are used for abnormal Noradrenaline?

A

Reuptake blockers
-e.g. tricyclic drugs are antidepressants

MOA inhibitors are antidepressants

38
Q

What drugs are used for abnormal Serotonin; 5-HT?

A

Selective serotonin reuptake inhibitors (SSRIs) are antidepressants.

Triptans (selective 5-HT) used for the treatment of migraine

39
Q

What drugs are used for abnormal GABA?

A

GABA agonists are anti-epilepsy drugs.

They also have anti-anxiety properties

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