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Life Control > Pharmacology of neurotransmitters > Flashcards

Pharmacology of neurotransmitters Flashcards

1
Q

What are the main types of inhibitory and stimulatory neurotransmitters in the CNS?

A

STIMULATORY
glutamate

INHIBITORY
GABA

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2
Q

Why is brain pharmacology complicated?

A

one neurotransmitter has multiple has effects
with many pathways that are interconnected

this is also why drugs modulating CNS pharma are complex and numerous

(unlike peripheral pharmacology)

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3
Q

What are the association between dopamine and disease?

A

PARKINSON’S DISEASE
reduced dopamine

PSYCHOSIS, SCHIZOPHRENIA
increased dopamine

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4
Q

What is the association between serotonin and disease?

A 
DEPRESSION
reduced serotonin (5-HT)
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5
Q

What is the association between GABA and disease?

A

SEDATION, ANXIETY

increased GABA

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6
Q

What are the main features of a neurotransmitter?

A
  • synthesised in neurons
  • stored in vesicles and secreted from neurons
  • identity of action: stimulate neurons/receptors should be the same effect as applying NT
  • receptors for NT: use of agonists or antagonists
  • termination of response: uptake transporters or enzymes
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7
Q

What are the different types of neurotransmitters in the CNS?

A

AMINO ACIDS
fast mechanism
excitatory, inhibitory

AMINES
slower response than AAs
more involved with modulation of the excitation/inhibition response rather than binary response

NEUROTROPHIC AGENTS
not technically NTs
work in conjunction with NTs to modulate their effects
sometimes these are also secreted from other non-neural cells e.g. immune cells

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8
Q

What are the AMINO ACID types of neurotransmitters in the CNS?

A

EXCITATORY
glutamate
aspartate

INHIBITORY
GABA
glycine

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9
Q

What is GABA?

A

-> key inhibitory NT

= gamma-amino-butyric -acid

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10
Q

What are the AMINE types of neurotransmitters in the CNS?

A
  • dopamine

- serotonin (5-HT)

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11
Q

What are types of neurotrophic agents active in the CNS?

A
  • Substance P
  • calcitonin-gene related peptide (CGRP)
  • vasoactive intestinal peptide (VIP)
  • brain-derived neurotrophic factor (BDNF)

released from neurones + other cell types

can act at pre- or post-synaptic sites (do not conform to normal NT rules)

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12
Q

The synthesis of which 2 NTs are interconnected?

A

glutamate + GABA

this means that changes in glutamate will potentially affect GABA function too

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13
Q

How is glutamate made?

A

(= NT)

  • converted from glutamine released from glial cells, which then enter the neurones
  • made from glucose via the Krebs cycle

(so if increased rate of Krebs cycle, increase ate of glutamate synthesis)

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14
Q

How is GABA made?

A

From glutamate

via glutamic acid decarboxylase (enzyme is required in GABAergic neurons)

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15
Q

What is glutamate?

A

major EXCITATORY NT in CNS
distributed through the CNS

Binds to:

1) ligand-gated ion channel receptors (fast)
e. g. AMPA, NMDA and kainate
- > binding causes Na+/Ca2+ influx and membrane depolarisation and AP firing

2) GPCR: mGlu (slower response)

both will induce AP firing in subsequent neuron via binding at the post-synaptic membrane

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16
Q

How is glutamate involved in learning and memory?

A

SYNAPTIC PLASTICITY is the basis for learning/memory

high frequency stimulation of neurons, enhances the synaptic activity

Glutamate -> NMDA -> Ca2+ influx -> synapse function modulated -> basis for learning and memory (hippocampus)

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17
Q

What is glutamate excitotoxicity?

A

Glutamate is toxic when overexpressed to abundant in the synapses

Removed quickly (glutamate uptake transporters) into glial cells or converted into glutamine in astrocytes

Stroke: ischaemia -> cell death -> necrotic release of glutamate -> hyper-stimulation -> glial cell toxicity

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18
Q

What is the pharma potential of glutamate?

A

interesting for neurodegeneration

but may have huge side effects

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19
Q

What is ketamine?

A

non-competitive block/inhibitor of NDMA receptors
(blocks effects of glutamate binding)

  • anaesthesia
  • recreational
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20
Q

What is GABA?

A

major INHIBITORY NT in CNS
mainly found in interneurones

Binds to:

1) ligand gated: GABA-A
2) GPCR: GABA-B

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21
Q

What proportion of CNS is GABAergic?

A

30% of all synapses are GABAergic

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22
Q

What is the purpose of having inhibitory interneurones in the CNS?

A

provides distinction between different types of excitation

does this by breaking down neural info into levels of excitation (relative to inhibitory signals)

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23
Q

How does GABA-A signalling work?

A

binds to ligand-gated ion channels

Causes Cl- influx: results in hyperpolarisation -> termination of AP (inhibition)

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24
Q

How does GABA-B signalling work?

A

binds to GPCRs

causes opening of K+ channels and therefore closes Ca2+ channels
-> hyperpolarisation -> termination of AP (inhibition)

25
Q

How does glycine NT work?

A

inhibitory NT, important in the spinal cord

binds to a ligand-gated receptor/ion channel: causes Cl- influx -> hyperpolarisation -> AP termination

26
Q

What are the effects of inhibitory NT binding at the pre-synaptic terminal?

A

reduced release of excitatory NTs

27
Q

How do benzodiazepines work?

A

increased activity go GABA-A receptors (agonist)

increased Cl- influx (channel activity increases)

  • used for sedation, anxiety
28
Q

How do barbiturates work?

A

similar mechanism to benzodiazepines (GABA-A agonist, increased Cl- flux -> hyperpolarisation -> inhibition of AP)

not used as much due to toxic effects

29
Q

How does strychnine world?

A

glycine receptor antagonist

reduced Cl- activity (Cl- influx) -> reduced effect of glycine -> reduced inhibitory transmission -> (indirectly more excitatory transmission)

SE include: muscle spasm, asphyxiation (very toxic)

30
Q

How does tetanus toxin work?

A

= glycine receptor antagonist

reduced glycine release -> less inhibitory transmission -> (indirectly more excitatory transmission)

effects: muscle spasms, lock-jaw

31
Q

What are the associations between dopamine and disease?

A

PSYCHOTIC DISORDERS
increased dopamine

PARKINSON'S DISEASE
reduced dopamine (neurons)

ADDICTION
changes to dopamine levels

32
Q

Where does dopamine work in the CNS?

A

Projections of dopaminergic neurons in CORPUS STRIATUM.

These neurons travel to:

  • PRL (anterior pituitary)
  • motor cortex (cerebellum)
  • addiction, reward, dependence (temporal lobe)
33
Q

What does dopamine bind to?

A

5 known dopamine receptors: D1-D5

All GPCRs

34
Q

How is dopamine synthesised?

A

FROM L-TYR

tyrosine -> DOPA
-> tyr hydroxylase (rate-limiting step)

DOPA -> dopamine
-> DOPA decarboxylase (DCC)

35
Q

How is dopamine broken down?

A

2 pathways:

  • Monoamine oxidase (MAO)
  • catechol-O-methyltransferase (COMT)
36
Q

How may dopamine levels be increased pharmacologically?

A
  • increase synthesis from L-Tyr

- reduce catabolism (MAOi or COMTi)

37
Q

Why is it insufficient to prescribe oral dopamine on its own (Levodopa) for Parkinson’s disease?

A

oral DOPA will undergo first pass metabolism in the liver

and will be converted to dopamine peripherally and catabolised before reaching the brain

Can’t just increase the dose, because then you will just see the peripheral effects as side effects

38
Q

What is oral dopamine usually prescribed with for Parkinson’s disease?

A
  • Peripheral DDC inhibitor (Cardidopa), does not cross BBB
    this means that DOPA will only be converted to dopamine in the brain
  • COMT inhibitor (entacapone)
    prevents dopamine metabolism (systemically)
39
Q

Why do only a 1/3rd of PD’s patients have improvements after 5 yr?

A

whilst oral DOPA + DDCi + COMTi is effective (80% pt improvement)

this effect reduces over time
(thought to be due to build up of tolerance and high circulating dopamine altering how neurons work- plasticity)

side effects: dyskinesia, mood changes, fluctuation in clinical state (bad-to-good-to-bad)

N+V, anorexia, hypotension

40
Q

Which dopamine agonists are used for Parkinson’s Rx?

A 
BROMOCRIPTINE
(D1/D2 selective)
often first-line Rx
few motor adverse effects
not as effective as L-DOPA
SE: excessive vomiting, sleepiness (somnolence)
ROPINIROLE
(D2/3 selective)
newer drug
less side effects
evidence for changing behaviour: may stimulate reward system (temporal lobe) e.g. gambling, sexual disinhibition
41
Q

What is somnolence?

A

sleeping for an excessively long period of type

different to hypersomnia

42
Q

What are MAO-B inhibitors?

A

used to Rx Parkinson’s disease
e.g. SELEGILINE
MAO-B specific to CNS (not in periphery)
therefore blocking MAO-B does not cause cheese reaction

Levedopa + selegiline combo is better than levodopa alone (for Sx relief and prolonging life)

43
Q

What is a cheese reaction?

A

HYPERACUTE HYPERTENSION (hypertensive crisis)

cheese/chocolate contain high [TYRAMINE] which gets exchanged for NA in sympathetic nerves
causes hyperstimuatopn of a1 receptors and hypertensive crisis
normally tyramine is catabolised by MAO, but if there are MAOi on board, the tyramine will accumulate

44
Q

Why are dopamine antagonists used?

A

strong correlation between increased [dopamine] and psychosis/schizophrenia

45
Q

What is haloperidol?

A

typical anti-psychotic drug, selective D2 receptor antagonist

Significant SE (extra-pyramidal):

  • acute dystonia (PD-like)
  • akathisia (restlessness)
  • tardive dyskinesia (pointless random movements, difficult to reverse)
  • Hyper-PRL reaction (gynaecomastia and weight gain since no negative feedback)
46
Q

How does Olanzapine work?

A

Atypical anti-psychotics
D2 and 5-HT2 receptor antagonist
less extrapyramidal effects
can cause metabolic issues: weight gain, DM, lipid profile changes

47
Q

What are extra-pyramidal effects?

usually in dopamine modulation

A
  • acute dystonia (PD-like)
  • akathisia (restlessness)
  • tardive dyskinesia (pointless random movements, difficult to reverse)
  • Hyper-PRL reaction (gynaecomastia and weight gain since no negative feedback)
48
Q

Why do anti-psychotic drugs often have compliance issues?

A

often many side effects
and take a long time to take effect

What is the solution? Depot administration?

49
Q

What is serotonin?

A

NT: strong link to mood disorders (depression, anxiety)

14 5-HT receptors (13 GPCRs, 1 ligand-gated)

5-HT3 binds to ligand-gated ion channel (MoA for Endansentron)

50
Q

Where are serotoninergic neurons located?

A

originate in the midbrain but travel into multiple parts of the cortexes (many effects)

multiple functions: behaviour, mood, sleep, feeding

also linked to endogenous analgesia pathway in descending spinal cord

51
Q

What is stress-induced analgesia?

A

Descending pathways of spinal cord capable fo inhibiting pain signals entering the spinal cord due to 5-HT signalling (there is sensing of pain, but no transmission to the brain means there is no interpretation of pain)

e.g. in trauma

52
Q

How is serotonin synthesised?

A

From TRYPTOPHAN (essential dietary AA)

tryptophan -> 5-hydroxytryptophan
(tryptophanhydroxylase)

5-hydroxytryptophan -> 5-HT
(5-hydroxytryptophan decarboxylase)

53
Q

How is serotonin signal catabolised?

A

taken up from cleft into the presynaptic terminal (uptake transporter)

5-HT not degraded directly in synaptic cleft

broken down by MAO in presynaptic terminal

54
Q

What are the associations between serotonin (5-HT) and disease?

A

MOOD (AFFECTIVE) DISORDERS

reduced 5-HT

55
Q

How do SSRIs work?

A

anti-depressants
= selective serotonin re-uptake inhibitors
e.g. fluoxetine

reduces 5-HT reuptake into pre-synaptic terminals (increases the [5-HT] in the synapse)

used to treat moderate-severe depression, panic disorder, OCD

safer in OD

56
Q

How do tricyclic anti-depressants work?

A

e.g. amitryptyline

used to Rx moderate-severe depression, neuropathic pain (low doses)

works by: 5-HT and NA reuptake inhibitor

57
Q

What other drugs target the 5-HT system?

A 
MAO INHIBITORS
e.g. phenelzine
anti-depressants 
can trigger cheese reaction 
not used that much

SUMATRIPTAN
5-HT1B/D agonist
vasoconstriction
Rx for migraine

BUSPIRONE
5-HT1A agonist
Rx anxiety

ONDANSENTRON
5-HT3 agonist
Anti-emetic

ATYPICAL ANTI-PSYCHOTICS
e.g. olanzipine
also blocs 5-HT2 receptors

58
Q

How are 5-HT agonists used to treat neuropathic pain?

A

utilises the stress-induced analgesia mechanism

increases 5-HT signalling in descending pathway of spinal cord
therefore blocks sensory pain signals the brain
no interpretation
reduced pain

(used at lower doses for this application)

Life Control (25 decks)

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