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Nervous System > Applied Neuropharmacology > Flashcards

Applied Neuropharmacology Flashcards

1
Q

What are the steps in synaptic transmission?

A
  1. Synthesis and packaging of neurotransmitter (usually) in presynaptic terminals
  2. Na+ action potential invades terminal (action potential along axon)
  3. Activates voltage gated Ca2+-channels (flows in)
  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
    * ACh is the exception as its inactivated by enzymatic breakdown in synaptic cleft
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2
Q

What is the difference between ionotropic and metabotropic receptors?

A

Ionotropic receptors change shape when a neurotransmitter binds, creating a channel for molecules to travel through.

Metabotropic receptor activation result in the opening of channels somewhere else on the membrane

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3
Q

List eight ways drugs can reduce synaptic transmission

A
  • Inhibit synthesis and packaging of neurotransmitter
  • Activate presynaptic inhibitory receptors
  • Block voltage gated Na+ channels
  • Block post-synaptic receptors (i.e. non-comp/competitive antagonists)
  • Block voltage-gated Ca2+ channels
  • Increase breakdown of transmitter
  • Block release machinery
  • Increase uptake of transmitter
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4
Q

What is the effect of local anaesthetics?

A

Block voltage gated Na channels and therefore all action potentials (not too useful)

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5
Q

What is the effect of spider toxins?

A

Block the voltage gated Ca2+ channels and therefore block all transmitter release (not too useful)

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6
Q

What is the effect of botox?

A

Block the release machinery and therefore would block all transmitter release (not too useful)

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7
Q

List five ways drugs can increase synaptic transmission

A
  • Increase synthesis and packaging of neurotransmitter (i.e. increasing availability of precursors)
  • Activate post-synaptic receptors with an agonist
  • Potentiate effect of transmitter on post-synaptic receptors (i.e. increase channel open time)
  • Block breakdown of transmitter
  • Block take of transmitter
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8
Q

What are the effects of allosteric drugs?

A

Activates the post-synaptic receptor, but potentiates the effects of the endogenous transmitter

I.e. benzodiazepines and barbiturates on GABA receptors

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9
Q

Give an example of a drug which blocks breakdown of transmitter

A

Anticholinesterases on ACh

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10
Q

Name six different types of neurotransmitters

A
  • Acetylcholine
  • Monoamines
  • Amino acids
  • Purines
  • Neuropeptides
  • NO
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11
Q

Give examples of monoamines

A
  • Noradrenaline
  • Dopamine
  • Serotonin (5-HT)
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12
Q

Give examples of amino acids

A
  • Glutamate
  • GABA
  • Glycine
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13
Q

Give examples of purine

A
  • ATP

* Adenosine

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14
Q

Give examples of neuropeptides

A
  • Endorphins
  • CCK
  • Substance P
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15
Q

What are the consequences of there bring a limited range of neurotransmitters?

A

A single neurotransmitter has multiple functions in different regions

Often in the brain and in the peripheral nervous system – separated by the blood brain barrier

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16
Q

What are the features of each neurotransmitter?

A
  • Its own distribution
  • Its own range of receptors it acts on
  • It own range of functions in different regions (some separated by the blood brain barrier)
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17
Q

What are the different anatomical distribution of dopamine (DA) in the brain?

A
  • Mesocortical pathway
  • Nigrostriatal pathway
  • Tubero-infundibular pathway
  • Mesolimbic pathway
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18
Q

What is the mesocortical pathway?

A

Dopaminergic pathway which connects the ventral tegmental area (of midbrain) and the prefrontal cortex

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19
Q

What is the nigrostriatal pathway?

A

Dopaminergic pathway which connects the susbtantia nigra and corpus striatum (basal ganglia)

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20
Q

What is the tubero-infundibular pathway?

A

Dopaminergic pathway which connects the arcuate nucleus to the median eminence (both hypothalamus)

21
Q

What is the mesolimbic pathway?

A

Dopaminergic pathway which connects the ventral tegmental (midbrain), to the ventral striatum (basal ganglia)

22
Q

What physiological functions are affected by dopamine (DA)?

A
  • Voluntary movement
  • Emotions / reward
  • Vomiting
23
Q

What occurs in Parkinson’s disease (wrt dopamine)?

A
  • Degeneration of DA cells in the SN (nigrostriatal)

* DA deficiency in the basal ganglia

24
Q

What are the steps in dopamine synthesis?

A
  1. Glycine –>
  2. Alanine –>
  3. Phenylalanine –>
  4. Tyrosine –> (via tyrosine hydroxylase)
  5. Dihydroxyphenylalanine (DOPA) –> (via aromatic aa decarboxylase)
  6. Dopamine
25
Q

How can DA synthesis be modulated in vivo?

A

Pharmacologically blocking aromatic aa decarboxylase and tyrosine hydroxylase can be lost through degeneration

26
Q

How many different types of dopamine receptors are there?

A 
Metabotropic receptors:
• D1 - activate adenylate cyclase 
• D2 - inhibit adenylate cyclase 
• D3 - inhibit adenylate cyclase 
• D4 - inhibit adenylate cyclase 
• D5 - activate adenylate cyclase
27
Q

Why can dopamine not evoke fast EPSPs or IPSPs?

A

As does not have any ionotropic receptors

28
Q

Why can drugs that target dopamine be useful for a specific effect?

A

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

Therefore, a selective agonist or antagonist could produce a specific therapeutically useful effect

29
Q

What is the clinical presentation of Parkinsons?

A

Stiffness, slow movement, change in posture, tremor

30
Q

What is dopamine broken down into?

A

Homovanillic acid

31
Q

What are the two different pathways of dopamine breakdown into homovanillic acid?

A

DA –> dihydroxyphenylacetic acid (DOPAC) –> homovanillic acid

DA –> 3-methoxytryptamine (3-MT) –> homovanillic acid

32
Q

Name two classifications of dopaminergic drugs

A

DA precursor and DA agonists

33
Q

Give an example of a DA precursor

A

Levodopa

34
Q

Give examples of DA agonists

A 
• Ergots; 
bromocriptine, pergolide, cabergoline
• Non-ergots; 
ronipirole, pramipexole, rotigotine 
• Ampomorphine

These drugs can improve some symptoms of PD

35
Q

Name some enzyme inhibitors in the dopamine pathway

A
  • Peripheral AAAD inhibitors eg carbidopa, benserazide
  • MAOB inhibitors (prevent breakdown of DA) eg selegiline, rasagiline, safinamide
  • COMT inhibitors (prevent breakdown of levodopa) eg entacapone, tolcapone
36
Q

How does peripheral AAAD inhibitors work?

A

↓ peripheral side-effects of levodopa and allows a greater proportion of the oral dose to reach the CNS

37
Q

How do MAOB and COMT inhibitors work?

A

↓ metabolism of dopamine and so increase effectiveness of levodopa.

38
Q

What are the side effects of dopaminergic drugs?

A 
Worsen or cause:
• Nausea
• Vomiting
• Psychosis
• Impulsivity / abnormal behaviours
39
Q

What do dopminergic drugs improve in PD and what do they fail to help?

A

Some motor features of Parkinson’s 
e.g. limb rigidity & bradykinesia, tremor

But fail to improve ‘midline’ features i.e. dysathria, balance, cognition

40
Q

What do dopamine antagonists improve and worsen?

A
  • Nausea
  • Vomiting
  • Psychosis

But worsen Parkinsonism.

41
Q

Why should DA antagonist antiemetics not be used in PD?

A

It ill worsen PD as although the area postrema (vomiting centre) in the medulla if functionally OUTSIDE the BBB, the DA antagonists are still able to cross the blood brain barrier

42
Q

What DA antagonist antiemetic does NOT cross the BBB?

A

Domperidone

43
Q

What are the properties of domperidone?

A
  • DA antagonist
  • Anti-emetic
  • Does not cross BBB
  • No antipsychotic properties
  • Relatively safe to use in PD
  • Has permitted the therapeutic use of apomorphine (powerful emetic)
44
Q

What is dyskinesia?

A

Abnormality or impairment of voluntary movement

45
Q

What drugs cause dyskinesias?

A

Dopaminergic drugs –> dyskinesias “too much movement”

DA antagonists –> parkinsonism “not enough movement”

46
Q

What are the consequences of long term DA antagonist use?

A

• Antipsychotics / anti-dizziness
• Often cause parkinsonism
e.g. receptor blockade in basal ganglia
• Sometimes cause dyskinesias: Tardive dyskinesias (orofaciolingual)

47
Q

What are the actions of noradrenaline?

A
  • Reuptake blockers eg tricyclic drugs are antidepressants.

* MAO inhibitors are antidepressants.

48
Q

What are the actions of serotonin (5-HT)?

A
  • Selective serotonin reuptake inhibitors (SSRIs) are antidepressants.
  • Triptans (selective 5HT agonists) used for the treatment of migraine
49
Q

What are the actions of GABA?

A
  • GABA agonists are anti-epilepsy drugs.

* They also have anti-anxiety properties.

Nervous System (47 decks)

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