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Pharmacology II > Ion Channels and Pain > Flashcards

Ion Channels and Pain Flashcards

1
Q

5 receptor types

A 
Lipid-soluble ligand
Enzymatic reaction
Tyrosine Kinase activation
Ion channel activation
G protein-coupled receptor
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2
Q

Ion channels provide a _____ route for ions through _____ _____ membranes

A

Permeable

Hydrophobic lipid

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3
Q

Ion channels consist of ____ folded into ________

A

amino acids

complex structures

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4
Q

Ion channels are made from 3-6 similar ______ or ______

A

proteins

structural subunits

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5
Q

Can ion channels be selective to specific ions? non-selective?

A

Yes

Yes

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6
Q

Definition of gating

A

open and close in response to specific chemical, electrical or mechanical signals

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7
Q

Ion channels conduct ions across _____________

A

plasma membrane

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8
Q

Ion channels regulate ________ ________ of cells

A

membrane potential

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9
Q

5 types on ion channels

A 
Resting K+ channel
Voltage-gated channel
Ligand-gated channel
Signal-gated channel
Mechanically-gated channel
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10
Q

Ions that cross through voltage-gated channels?

A

Na+, K+, Ca2+, Cl-

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11
Q

How many transmembrane segments are in the voltage-gated ion channels?

A

6

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12
Q

Voltage-gated ion channels open in response to changes in what?

A

membrane potential

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13
Q

2 domains in voltage-gated ion channels?

A 
Voltage sensor domain (S1-4)
Pore Domain (S5-6)
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14
Q

3 major superfamilies on Ligand-Gated Ion channels?

A

Cys-Loop Receptors
Ionotropic Glutamate Receptors
P2X Receptors

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15
Q

Ligand-Gated Ion Channels : transmembrane domains are important for? (2)

A

pore formation

ion selectivity

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16
Q

Ligand-Gated Ion Channels : what is important for ligand binding? (determines which ligand can bind to it)

A

extracellular domains

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17
Q

Extracellular domain of Cys-Loop receptors?

A

Disulfide bridges of cysteine residues

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18
Q

Extracellular domain of Ionotropic Glutamate receptors?

A

Ligand binding domain (segment and 2)

N-terminal domain

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19
Q

Two ways a cell can sense a mechanical stimuli?

A

Direct gating by physical opening of channel

Indirect by activation of GPCR then opening of TRP channels

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20
Q

What happens in regard to action potential when activating a ligand-gated ion channel?

A

Opening, Na+ influx, nerve depolarisation

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21
Q

Effect of a mild mechanical stimulation

A

Opening of only a few ion channels, but firing isn’t highly activated, relatively few action potentials

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22
Q

Effect of noxious mechanical stimulation

A

Many ion channels open, nerve firing probability increased and multiple action potentials can be generated which means more firing of the nerves

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23
Q

Effect of noxious mechanical stimulation

A

Many ion channels open, nerve firing probability increased and multiple action potentials can be generated which means more firing of the nerves

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24
Q

Resting membrane potential value?

A

-70mV

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25
Q

Which complex helps the transport of cations and anions to normalize the membrane potential?

A

Na+/K+ exchange pump

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26
Q

Concentration gradients of Na+ and K+ in extracellular and intracellular?

A

Extracellular:
K + 4.5 mM
Na+ 145 mM

Intracellular
K+ 120 mM
Na+ 15 mM

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27
Q

What causes sodium to enter channel? what happens to action potential?

A

stimulus

depolarization (spike in voltage)

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28
Q

When sodium leave the cell and ion channel closes, what happens to action potential? What does this do to ADP-ATP?

A

repolarization

Exchange ATP for ADP

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29
Q

Example of Cys-Loop Channel?

A

Nicotinic Ach Receptor

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30
Q

Nicotinic Ach Receptor : subunits?

A

two alpha
one beta
one gamma
one delta

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31
Q

Nicotinic Ach Receptor requires how many Ach molecules for activation? Which ion influxes once the pore opens

A

2

Na+

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32
Q

Nicotinic Ach Receptor functions? (4)

A
  1. Skeletal muscle contraction
  2. Smooth muscle relaxation
  3. Inhibits cardiac muscle contraction
  4. Nerve depolarization
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33
Q

What dictates the location and pharmacology of Nicotinic Ach Receptors?

A

Subunit composition

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34
Q

What causes depolarizing blockade? (Nicotinic Ach Receptor)

A

Excess Ach and Nicotinic Receptor Agonists

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35
Q

Depolarizing blockade : what are the effects of continuous activation of nicotinic receptors?

A

Muscle excitation and fasiculations in myocytes and then flaccid paralysis

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36
Q

Depolarizing blockade : what are the effects of prolonged agonist bound nAchRs?

A

neuron desensitization

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37
Q

Depolarizing blockade : what are the effects of continuously depolarized membrane?

A

Affects inactivation of voltage-gated sodium channels (nerve less likely to fire)

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38
Q

nAch Receptors located where?

A

DRG

Dorsal horn of spinal cord

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39
Q

Ach sensitizes about 50% of ___ fibres for heat but not ________ pain

A

C

mechanical

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40
Q

Analgesics for nAch Receptors and Pain? (4)

They inhibit what? (2)

A

Botulinum toxin, alpha-7 blockers, epibatidine, nicotine

Inhibits inflammatory neuropeptide and cytokine release

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41
Q

GABAARs Cys-Loop Receptor : what type of receptor? allows passage of what ion?

A

Inhibitory (hyperpolarization)

Cl-

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42
Q

Composition of GABAAR?

A

Heteropentameter with variable subunits

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43
Q

GABAARs activated by what?

A

GABA

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44
Q

GABAARs are found where?

A

Dorsal horn of spinal cord

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45
Q

Roles of GABAAR? (2)

A

Inhibits pain transmission by hyperpolarizing second order neurons
Inhibits substance P release form primary afferent neurons

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46
Q

Which drugs potentiate GABA-mediated synaptic inhibition? (2)

A

Benzodiazepines

Barbiturates

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47
Q

GABA binds where on GABAAR?

A

alpha-beta interface

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48
Q

Benzodiazepines binds where on GABAAR?

A

alpha-gamma subunit interface (allosteric binding site)

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49
Q

Barbiturates interacts with what on GABAAR?

A

Pockets in the transmembrane domain

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50
Q

Acute pain?

A

warning system for harmful stimuli

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51
Q

chronic pain lasts more than _____ months and it is __________

A

3

maladaptive

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52
Q

the Nervous system can change in response to pain because it is _______

A

plastic

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53
Q

4 steps to the pain pathway

A
  1. Nociception
  2. Neurotransmission
  3. Sensation, Cognition, Emotion
  4. Neuromodulation
54
Q

5 types on fibres in the sensory nerves
Which one is unmyelinated?
Biggest to smallest diameter?
Biggest to smallest conduction velocity?

A 
A-alpha
A-beta
A-gamma
A-delta
C - unmyelinated

From top to bottom :

  • biggest to smallest diameter
  • fastest to slowest conduction velocity
55
Q

Function of A-alpha fibre

A

proprioception

56
Q

Function of A-beta fibre

A

mechanosensation

57
Q

Function of A-gamma fibre

A

Motor fibre to muscle spindle

58
Q

Function of A-delta fibre

A

mechanosensation nociception

59
Q

Function of C fibre

A

temperature nociception

60
Q

3 types of pain

A

Nociceptive
Inflammatory
Neuropathic

61
Q

5 factors that activate nociceptors

A 
Mechanical
Heat
Cold
Pathogens
Chemical
62
Q

What activates TPRV1 and what does this lead to?

A

Capsaicin
Mustard Oil
Formalin
H+

Opens channel, Na+ an Ca2+ enter free nerve ending, depolarisation

63
Q

What causes neuropathic pain in the periphery? (4)

A

Trauma
Metabolic
Infection
Chemo induced neuropathy

64
Q

What causes neuropathic pain centrally?

A

Spinal cord injury
Stroke
Multiple sclerosis

65
Q

3 classes on analgesics

A

Non-opioid analgesics
Opioid analgesics
Adjunct analgesics

66
Q

3 types of adjunct analgesics

A

Anti-convulsants
Anti-depressants
Biologics

67
Q

3 types of anti-depressants

A

TCAs
SSRIs
SNRIs

68
Q

TCAs are highly effective for _____ neuropathic pain

69
Q

Example of a TCA and what is their MOA?

A

Amitriptyline
Blocks neuronal uptake of NA and 5-HT in spinal cord, increases descending inhibition
Also blocks NMDA receptors, Na, K, Ca channels

70
Q

What is the major effect of Amitriptyline (TCA)?

A

Analgesic effect is independent of mood change

71
Q

Examples of SNRIs? (2)

A

Duloxetine

Venlafaxine

72
Q

Examples of SSRIs?

A

Fluoxetine

Fluvoxamine

73
Q

SSRIs have fewer side effects because of ___________

A

high selectivity

74
Q

SSRIs have low efficacy for __________ neuropathic pain

75
Q

SNRIs have fewer side-effects than TCAs because they __________________

A

do not block NMDA receptors

76
Q

More efficient : TCA, SSRIs of SNRIs?

A

TCA > SNRI > SSRI

77
Q

More side effects : TCA, SSRIs, or SNRIs>

A

TCA > SNRI > SSRI

78
Q

anti-convulsants are used for ______ and they interfere with _______

A

epilepsy

neuronal excitability

79
Q

2 examples of anticonvulsants?
Effective for which diseases? (3)
Side effects? (4)

A

gabapentin
pregabalin

Postherpetic neuralgia, diabetic neuralgia, fibromyalgia

Side-effects : drowsiness, dry mouth, weight gain, dizziness

80
Q

MOA of gabapentinoids?
What does it inhibit?
It also modulates what?

A

MOA : binds to alpha-2-delta subunit of Ca2+ channel

  • Inhibits release excitatory NTs
  • Also modulates Na, K activity : altered neuronal excitability
81
Q

Gabapentin is given ___

82
Q

Gabapentin reduced _____ in normal AND inflamed joints

A

mechanosensitivity

83
Q

In inflamed joints, gabapentin doesn’t seem to reduce __________

A

neuronal activity

84
Q

is gabapentin ideal for inflammatory pain?

85
Q

Inflammation may alter gabapentin binding to what?

A

alpha-2-delta subunit of Ca2+ channel

86
Q

Na+, K+ and Ca2+ are involved in nerve ________ and _______.

Also in electrical _________ along ______

A

depolarization
communication

transmission
axons

87
Q

Voltage-dependent conformational change in ion channels results in what?

A

open state

88
Q

Voltage-gated Sodium Channels (VGSC) :
Classification of VGSC?
Derived from what?

A

Tetrodotoxin (TTX)

Derived from puffer fish

89
Q

TTX sensitive channels are found where? (2)

A

Muscle, CNS

90
Q

TTX resistant channels are found where?

A

Some sensory neurones

91
Q

Types of VGSC? (9)

A

Nav1.1-Nav.9

92
Q

Which VGSC isoforms are involved in nociception?

A

Nav1.7, Nav1.8 and Nav1.9

93
Q

Which Nav isoforms are predominantly in the CNS?

A

Nav1.1, Nav1.2 and Nav1.3

94
Q

Where is Nav1.4 found? What is their role?

A

skeletal muscle

skeletal muscle contractility

95
Q

Where is Nav1.5 found? What is their role?

A

Heart

Cardiac function

96
Q

Where is Nav1.6 found?

A

Mainly in large diameter neurons, motor neurons, also in CNS

97
Q

Where are Nav1.7, Nav1.8 and Nav1.9 found?

98
Q

Which Nav isoforms have a slow inactivation rate?

A

Nav1.8 and Nav1.9

99
Q

Which Nav isoforms have a low TTX sensitivity?

A

Nav1.8 and Nav1.9

100
Q

Which Nav isoform has an intermediate TTX sensitivity?

101
Q

Which Nav isoforms are brain type sodium channels and unlikely to be involved in pain?

A

Nav1.1, Nav1.2, Nav1.3, Nav1.6

102
Q

Role of Nav1.7?

A

Peripheral sodium channel subtype. Excellent target for pain control

103
Q

Role of Nav1.8? (3)

A
  • Action potential electrogenesis
  • Redistribution along intact axons after nerve injury may promote sensory hypersensitivity
  • Excellent target for pain control
104
Q

Role of Nav1.9?

A

May modulate resting potential of DRG and response to subthreshold stimuli.

105
Q

Nav1.7 gain of function disease?

A

Mutation in SCN9A gene
Familial erythromelalgia
Burning, intense pain

106
Q

Nav1.7 loss of function disease?`

A

Loss of function of SCN9A gene
Congenital insensitivity to pain
Self harm, unknown injuries

107
Q

What is a local anaesthetic that acts on sodium channels?
Does is activate or inactivate Na channel?
Where does it bind?
Is it selective?

A

Lidocaine
Inactivation
Intracellular pore
Not selective

108
Q

What is an antidepressant that acts on sodium channels?
Inactivate or activate Na channel? Where does it bind?
Is it non selective for ______ subtypes so it can affect _____ and _____ activity

A
  • Amitriptyline
  • Interacts with local anaesthetic binding site and binds to inactivated channel, keeps them in inactive state
  • Na+ channel subtypes
  • Cardiac and skeletal muscle
109
Q

What is an anticonvulsant that acts on sodium channels?
It inhibits which Na+ channels? (2)
Non-selective for _____ subtypes so can affect _____ and ______ activity

A

Carbamazepine
Binds to inactive channel, keeping them in inactive state
-Inhibits TTX-resistant and TTX-sensitive Na+ channels
-Na+ channel subtypes
-Cardiac and skeletal muscle activity

110
Q

When testing NON-SELECTIVE VGSC blockers, do we get negative or positive side-effects?

A

Negative

Ex: cardiac arrhythmias

111
Q

When testing Nav1.8 blocker on joint pain, does it increase or decrease pain?

112
Q

Where do Nav1.8 blockers act?

A

in periphery

113
Q

Cav1.1 - Cav1.4

Tell me their current, inactivation and tissue localization

A

Cav1.1 : L, Fast, skeletal muscle
Cav1.2 : L, Fast, Cardiac Myocytes and Neurons
Cav1.3 : L, Fast, Cardiac Myocytes and Neurons
Cav1.4 : L, Fast, Retinal Cells

114
Q

Role of Cav1.1

A

Excitation contraction coupling

115
Q

Role of Cav1.2

A

Excitation-contraction coupling

Synaptic integration

116
Q

Role of Cav1.3

A

Cardiac pacemaker

NT release

117
Q

Role of Cav1.4

A

NT release from photoreceptors

118
Q

Cav2.1-2.3

Tell me their current, inactivation and tissue localization

A

Cav2.1 : P/Q, Slow, Neurons
Cav2.2 : N, Slow, Neurons
Cav2.3 : R, Slow Neurons

119
Q

Role of Cav2.1

A

NT release

120
Q

Role of Cav2.2

A

NT release

121
Q

Role of Cav2.3

A

Nerve firing

122
Q

Cav3.1-3.3

Tell me their current, inactivation and tissue localization

A

Cav3.1 : T, Fast, Neurons and Cardiac Myocytes
Cav3.2 : T, Fast, Neurons and Smooth muscle
Cav3.3 : T, Fast, Neurons

123
Q

Role of Cav3.1

A

Repetitive Nerve firing

Cardiac pacemaker

124
Q

Role of Cav3.2

A

Repetitive Nerve firing

Contractile response

125
Q

Role of Cav3.3

A

Repetitive Nerve firing

126
Q

Name 2 L-Type drugs that act of calcium channels

What do they do?

A

Nifedipine
Verapamil
Decrease substance P release and pain

127
Q

Name 2 N-type drugs that act on calcium channels, what do they do?

A

conotoxin : decreases substance P release and pain

Knockout animals : decreases inflammatory and neuropathic pain

128
Q

Name a P/Q type drug that acts of calcium channels

What does it do?

A

agatoxin : decreases substance P release and migraine

129
Q

Name a R type drug that acts of calcium channels

What does it do?

A

SNX-482

Decreases substance P release

130
Q

Name a T type drug that acts of calcium channels

What does it do?

A

Mibefradil

decreases pain

131
Q

How is a voltage gated calcium channel classified?

How is it subclassified?

A

Classified based on type of voltage required to activate them
Subclassified based on alpha-1 pore forming subunit structure and pharmacological properties

Pharmacology II (21 decks)

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