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Neuroscience > Neuropharmacology > Flashcards

Neuropharmacology Flashcards

1
Q

What are the roles of the proteins found in the pre-synaptic and post-synaptic complexes?

A
  • Neurotransmitter release
  • Activation of receptor
  • Action potential propagation
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2
Q

What are the receptors on the post-synaptic membrane at an excitatory synapse for glutamate?

A

AMPA

NMDA

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3
Q

What is a neurotransmitter?

A

A chemical substance that:

  • Is synthesised, stored, and released from neurons
  • Activates receptors to produce an effect on the post-synaptic cell
  • Has its action terminated
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4
Q

Why are neurotransmitters important?

A
  • Control behaviour

- Target for drug therapies

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5
Q

What are Inotropic Neurotransmitter Receptors?

A
  • Ligand gated ion channels

- Fast neurotransmission

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6
Q

What does an inhibitory Inotropic Neurotransmitter Receptor do?

A

Neurotransmitter causes chloride influx and hyperpolarisation

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7
Q

What does an excitatory Inotropic Neurotransmitter Receptor do?

A

Neurotransmitter causes sodium influx and depolarisation

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8
Q

What are the types of neurotransmitter receptors at the post-synaptic membrane?

A
  • Inotropic

- Metabotropic

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9
Q

What are Metabotropic Neurotransmitter Receptors?

A
  • Induction of second messenger systems

- Slow neurotransmission neuromodulation

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10
Q

Describe second messenger systems

A
  • Receptor coupled to G-protein
  • Activates intracellular enzyme systems to produce an intracellular signal, the second messenger
  • Affects often ion channels
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11
Q

What are the classes of neurotransmitters?

A
  • Amino acids
  • Biogenic Amines
  • Peptides
  • Others
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12
Q

What are the amino acid neurotransmitters?

A
  • Glutamate

- GABA

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13
Q

What are the Biogenic Amines neurotransmitters?

A
  • Acetylcholine

- Monoamines

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14
Q

What are the monoamines?

A
  • Serotonin

- Catecholamines

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15
Q

What are the catcholamines?

A
  • Dopamine
  • Noradrenaline/ norepinephrine
  • Adrenaline/ Epinephrine
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16
Q

What are the peptide neurotransmitters?

A

Substance P

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17
Q

What are the other neurotransmitters?

A

ATP
Nitric Oxide
(short acting)

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18
Q

What are agonists?

A

Drugs that occupy the receptors and activate them

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19
Q

What are antagonists?

A

Drugs that occupy the receptors but do not activate them. Block the receptor activation by agonists

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20
Q

What are the pathways that use glutamate?

A
  • Cortical association
  • Cortico-thalamic
  • Cortico-spinal
  • Basal ganglia
  • Hippocampal
  • Cerebellar
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21
Q

Describe glutamate

A
  • Excitatory neurotransmitter
  • Synthesised from glutamine in astrocytes in pre-synaptic neurone
  • Removed from synapse by glutamate transporters
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22
Q

What are the subtypes of glutamate receptor?

A
  • NMDA
  • AMPA and Kainate
  • Metabotropic
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23
Q

How can glutamate be an excitotoxin?

A
  • High levels of glutamate, NMDA or AMPA kill neurons (sustained activation of receptors)
  • Glutamate levels rise following stroke
  • Glutamate receptor antagonists reduce brain damage following experimental stroke
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24
Q

Describe how glutamate is important in memory and learning

A
  • High densities of NMDA and AMPA receptors in the hippocampus
  • Role for glutamate receptors in long term potentiation
  • Glutamate receptor antagonists inhibit long term potentiation and learning and memory;
  • AMPA receptor potentiators enhance LTP and learning and memory
25
Q

What does GABA stand for?

A

Gamma aminobutyric acid

26
Q

What is GABA?

A
  • GABA is the main inhibitory neurotransmitter of the CNS (although in some settings it can be excitatory).
  • GABA acts via ionotropic (GABAA) and metabotropic (GABAB) receptors, and modulates flow of Cl- ions across the membrane.
  • Some anti-epileptic drugs mimic the effects of GABA or increase bioavailability of GABA (eg gabapentin, vigabatrin)
27
Q

What are Benzodiazepines?

A
  • GABA inhibitory chloride channel

- Enhance effects of GABA= sedative, anxiolytic, anti-convulsant

28
Q

What are the sites of the GABA inotropic channel?

A
  • Barbiturate
  • Benzodiazepine
  • Neurosteroid
  • GABA
29
Q

What is another name for Serotonin?

A

5-HT (5-hydroxytryptamine)

30
Q

How is serotonin synthesised?

A
  • Tryptophan
  • 5-Hydroxytryptophan
  • 5-hydroxytryptamine (serotonin)
31
Q

How is serotonin metabolised?

A

Serotonin + monoamine oxidase = 5- Hydroxy indoleacetic acid

32
Q

What are the types of serotonin receptors?

A
  • 5-HT1 (metabotropic)
  • 5-HT2 (metabotropic)
  • 5-HT3 (ionotropic
33
Q

Describe the serotonin pathways/ projections

A
  • Originate in the raphe nuclei in the brainstem
  • Project throughout cerebral cortex, cerebellum and limbic system
  • Sleep-wake cycles
  • Mood and emotional behaviour
34
Q

How is serotonin important in the management of depression?

A
  • Tricyclic compounds= imipramine, block uptake of serotonin
  • Selective Uptake Inhibitors = fluoxetine (Prozac)
  • Monoamine Oxidase Inhibitors= phenelzine, reduce enzymatic degradation of serotonin
  • serotonin remains in cleft for longer, bioavailability increases
35
Q

How can the serotonin pathways be used clinically as drug targets?

A
  • Anti-depressants
  • Anti-emetics
  • Migraine (triptans)
36
Q

How is Acetylcholine synthesised and metabolised?

A
  • Choline and acetyl CoA
  • Broken down by acetylcholinesterase in synaptic cleft
  • Choline transported back into axon terminal and used to make more ACh
37
Q

Describe the ACh pathways in the brain

A
  • Nucleus of maynert
  • Amygdala
  • Caudate nucleus
  • Cerebral cortex
  • Hippocampus
  • Brainstem nucleus
  • Thalamus
38
Q

What disease is associated with loss of cholinergic pathways?

A

Alzheimer’s
Reductions particularly in frontal and temporal cortices
-Reduction in ACh transferase activity

39
Q

What drugs are used in Alzheimer’s and what are the limitations of them?

A

ACE inhibitors= donepezil, rivastigmine, galantamine, tacrine (first)

  • Gradual loss of efficacy
  • Narrow therapeutic index
  • Limited range of effects on cognition and behaviour
  • Effective only in mild to moderate AD= slow symptoms but not curative
40
Q

What are the classic pathological features of AD?

A
  • Frontal and temporal atrophy
  • Beta-amyloid plaques
  • Neurofibrillary tangles
  • Localised to hippocampus and cortex
41
Q

What is the Amyloid pathway in AD?

A

-Amyloid is a component of amyloid precursor protein
=Integral transmembrane protein
=Axonally transported
=Synaptic transmission, neuroprotectant

42
Q

How is amyloid precursor protein processed in pathways?

A
  • Non amyloidogenic pathway= APP cleaved by a-secretase, products not pathogenic (amyloidogenic)
  • Amyloidogenic pathway= cleaved by beta-secretase, gamma-secretase (mixture of enzymes) cleaves one of the APP fragments into amyloidogenic fragment= beta amyloid (accumulates in brain parenchyma in AD)
43
Q

How do mutations in APP cause fAD?

A

Familial AD
Rare, account for less than 1%
Approx. 25 mutations

44
Q

How can beta amyloid be a drug target?

A

Bapineuzumab
Antibody targeted against amyloid beta (passive immunotherapy)
Might bind to cortical amyloid beta and facilitate clearance
PET Scan

45
Q

What are the clinical results of beta-amyloid immunisation?

A
  • Reduces amyloid load and prevents cognitive decline in mice
  • Reduces amyloid load but no improvement in CNA function in humans
  • In the future, better immunisation earlier in disease, target subgroups
46
Q

Describe dopamine synthesis

A 
Tyrosine 
(tyrosine hydroxylase)
DOPA
(dopa decarboxylase)
Dopamine
47
Q

Describe dopamine metabolism

A 
Dopamine
(dopamine beta hydroxylase)
Noradrenaline
/
(monoamine oxidase)
DOPAC
48
Q

What are the main pathways in dopaminergic neurotransmission?

A

Nigrostriatal Projections
Substantia nigra to basal ganglia
Involved in movement

49
Q

How is dopamine associated with Parkinson’s disease?

A
  • Degeneration of dopamine pathways in the basal ganglia/ substantia nigra
  • Treatment by enhancing dopamine levels (L-DOPA)
  • Adverse effects= psychosis
50
Q

Describe the mesolimbic projections in dopaminergic neurotransmission

A
  • Dopamine projections to the limbic system and cortex= reward, addiction
  • Increased dopamine function in the frontal cortex associated with schizophrenia
51
Q

What drugs are used in schizophrenia?

A

-Neuroleptics
=Chlorpromazine and related antipsychotics
=Dopamine receptor antagonists/ blocker
-Adverse effects= Parkinsonian syndrome

52
Q

What is the blood brain barrier?

A
  • Blood brain barrier - dynamic interface
  • Separates the brain from the circulatory system (endothelium of capillaries and astrocyte foot processes)
  • Protects the central nervous system from potentially harmful chemicals
  • Regulates transport of essential molecules and maintains a stable environment
53
Q

What is the role of the blood brain barrier?

A

Precise regulation of the local ionic microenvironment around axons and synapses is critical for reliable neuronal signalling

54
Q

What are the cellular components of the BBB?

A

-Physical barrier – tight junctions on endothelial cells
=Seal aqueous paracellular diffusion between cells
-Pericytes
-Astrocyte end foot processes

55
Q

What can cross the BBB?

A
  • Lipid soluble agents, aqueous pathways water soluble agents
  • Transcellular lipophilic pathways (cell membranes)
  • Transport carriers= glucose, amino acids
  • Receptor mediated endocytosis and transcytosis= insulin
56
Q

How are drugs designed to cross the BBB?

A
  • Almost all drugs for the brain presently in clinical practice are lipid soluble small molecules
  • Criteria for crossing BBB:
    (1) MW <400 Da threshold
    (2) high lipid solubility, ie. low hydrogen bonding (≤7 hydrogen bonds)
57
Q

What are the problems and solutions for how the BBB relates to pharmacological management of Parkinson’s?

A

-Dopamine too large to cross BBB
=L-Dopa (precursor) will cross via protein transport carrier (large neutral amino acid carrier)
*DOC and COMT inhibitors to prevent peripheral breakdown of levodopa
*MAO inhibitors to prevent breakdown of dopamine
*Dopamine agonists

58
Q

What is Carbidopa-Levadopa combination therapy?

A
  • L-dopa crosses BBB
  • Carbidopa doesn’t cross BBB but helps prevent L-dopa breakdown in periphery
  • Carbidopa inhibits DOPA-decarboxylase (DDC in brain and periphery)
59
Q

What are the ways of drug administration that penetrate the BBB?

A

-Intrathecal drug administration:
=Baclofen for spasticity in multiple sclerosis
=Only a small proportion of oral baclofen penetrates brain/spinal cord
=Intrathecal pump in subarachnoid space in lower back administers drug directly into CSF
-Experimental BBB opening
=Opening of the BBB using intracarotid infusion of hyperosmolar solutions
=Effective delivery of chemotherapy drugs for brain tumours (metastatic carcinomas)
-Future approaches= Intranasal drug administration, Nanoparticles

Neuroscience (33 decks)

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