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MODA > Dr Hiley - PNS > Flashcards

Dr Hiley - PNS Flashcards

0
Q

What is the synaptic vesicle cycle?

A

1) Uptake of transmitter release
2) Synaptic vesicles move to active zone
3) Vesicles dock to the plasma membrane
4) Vesicles undergo ATP-dependent pre-fusion
5) Ca2+ triggers completion of fusion
6) Vesicles retrieved by endocytosis
7) Coated vesicles shed coat and recycle to the interior of nerve terminal
8) Empty vesicles can either refill of pass through an endosomal intermediary sorting station

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1
Q

What is the synaptic structure of the ANS?

A

Terminal varicose axon branches that form a network in and around the effector cells

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2
Q

Which vesicular proteins are involved in neurotransmitter release?

A

v-SNAREs and synaptobrevin

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3
Q

Which terminal proteins are involved in neurotransmitter release?

A

t-SNAREs, SNAP-25 and syntaxin

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4
Q

Tetanus toxin?

A

Targets synaptobrevin

Stops release of transmitter from inhibitory interneurons
=Motor neuron more excitable = tetani

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5
Q

What is the target of botulinum B, D, F and G?

A

Synaptobrevin

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6
Q

Which botulinum toxins target synaptobrevin?

A

B, D, F and G

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7
Q

What do botulinum toxins A and E target?

A

SNAP-25

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8
Q

Which botulinum toxins target SNAP-25?

A

A & E

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9
Q

What does botulinum C1 target?

A

Syntaxin and SNAP-225

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10
Q

Which botulinum toxin targets syntaxin and SNAP-25

A

C1

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11
Q

Botulinum toxin?

A

Attack cholinergic neurons

Heavy chain - C-terminus binds to a glycoside and N-terminus translocates light chain

Light chain - Peptidase which cleaves SNARE

=Muscles weakness and ANS stimulation

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12
Q

What is the role of synaptotagmin?

A

Ca2+ sensor

Binds syntaxin during membrane fusion

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13
Q

What are synapsins?

A

Proteins on the surface of the vesicles which links them to the cytoskeleton (regulated by phosphorylation)

PKA/CaM Kinase II phosphorylation causes vesicular dissociation

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14
Q

What are the two kinds of synaptic plasticity?

A

Depression and Facilitation

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15
Q

What is synaptic depression?

A

Depletion of neurotransmitter after repeated stimulation

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16
Q

What is synaptic facilitation?

A

Ca2+ builds up as its entry is too fast for removal

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17
Q

Which aspects of the PNS can drugs act upon?

A
  • Neurotransmitters (NTs)
  • Synthesis of NTs
  • Storage of NTs
  • Release of NTs
  • Breakdown of NTs
  • Uptake of NTs
  • Activation of receptors
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18
Q

Draw Cholinergic transmission

A

Well done have a gold star

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19
Q

What is the rate limiting step of ACh synthesis?

A

Choline uptake

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20
Q

Hemicholium?

A

Blocks choline uptake by binding to transporter

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21
Q

Trimethylcholine?

A

Acts as a competitive substrate to choline in ACh synthesis

Acetylated to acetyltriethylcholine (released instead of ACh)

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22
Q

Vesamicol?

A

Block the vesicle transport (VAChT)

Inhibition is non-competitive and reversible

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23
Q

β-Bungarotoxin

A

Acts via a phospholipase A2 and localises to the membrane by a K+ channel-binding moiety

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24
Q

α-Latrotoxin

A

Black widow spider venom
Targets neurexins, latrophilin receptors, protein tyrosine phosphatase-σ
Τetramer forms ion pore = Ca2+ entry

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25
Q

Where is acetylcholinesterase found?

A

Soluble presynaptically and bound to the post synaptic membrane

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26
Q

Where is butyrylcholinesterase found?

A

Predominantly a plasma enzyme, also found in quantities in skin, brain and gut

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27
Q

With which Ach receptors does α-bungarotoxin interact?

A

Binds to brain (α7)5

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28
Q

What are the compositions of the striated muscles ACh receptors?

A

(α1)2β1δε

(α1)2β1δγ

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29
Q

What is the composition of the ACh receptors in the autonomic ganglion?

A

(α3)2(β4)3

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30
Q

What is the composition of the ACh receptors in the brain?

A

(α4)2(β2)3
Some (α3)2(β4)3
(α7)5

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31
Q

What are the phase of nicotine action?

A

Phase I block - Cells are depolarised

  • VGCs are refractory
  • Cell unresponsive to stimulation

Phase II block - cells repolarise

  • Neuron becomes electrically re-exitable
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32
Q

Trimetaphan

A

Competitive ACh receptor antagonist

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33
Q

Mecamylamine?

A

Non-competitive ACh receptor antagonist

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34
Q

Hexamethonium

A

Non-competitive ACh receptor antagonist

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35
Q

What effect does increasing the chain length have on hexamethonium’s action?

A

Changes its selectivity between ganglion and nmj

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36
Q

What were the side effects of hexamethonium?

A

Loss of sympathetic tone to blood vessels = hypotension
Loss of CV reflexes = Fainting
Inhibition of secretion = Dry skin and mouth
GI paralysis

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37
Q

D-Tubocurarine

A

ACh competitive antagonist

= flaccid paralysis

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38
Q

Atracurium

A

ACh competitive antagonist

Ester bond = spontaneous breakdown and hydrolysis by plasma esterases

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39
Q

Pancuronium

A

Competitive antagonist of the ACh receptor

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40
Q

Decamethonium

A

ACh agonist

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41
Q

What are the two phases of depolarising blocker action?

A

Phase I - Depolarising block = spastic paralysis
(short lived on focally-innervated muscles)

Phase 2 -Desensitisation block in focally-innervated muscles = flaccid paralysis

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42
Q

What effect do antiCHE and non-depolarising blockers have on Phase 1 of depolarising blockers action?

A

Phase 1 is deepened by antiCHE and reversed with non-depolarising blockers

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43
Q

What effect do antiCHE and curare-like drugs have on Phase 2 of depolarising blockers action?

A

Reversed by antiCHE and deepened by curare-like drugs

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44
Q

What are the 3 main subtypes of the muscarinic ACh receptor and which G protein type are they coupled to?

A

M1 - Gq
M2 - Gi
M3 - Gq

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45
Q

McN-A-343

A

Cell-specific stimulator of muscarinic receptors in ganglionic neurons

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46
Q

How do M1 and M3 signal?

A

Through the generation of IP3 and DAG

M1 also inhibits K+ conductance
M3 receptor stimulation increases [Ca2+]i

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47
Q

How does the M2 receptor function?

A

Gi inhibits adenylyl cyclase = decrease in cAMP
=Decreased phosphorylation of VGCC
=Decreased excitability of heart muscle/transmitter release

βγ subunit opens GIRK in pacemaker tissue
= decreased heart rate

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48
Q

Bethanecol?

A

Muscarinic receptor agonist used for urinary retention

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49
Q

Pilocarpine?

A

Muscarinic receptor agonist used in the treatment of glaucoma (contracts ciliary muscles)

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50
Q

Pirenzipine

A

Selective M1 antagonist

Decrease gastric acid secretion
effect on local ganglion rather than M3 receptors of oxyntic

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51
Q

Tripitramine

A

Selective M2 antagonist

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52
Q

Darifenacin?

A

Selective M3 antagonist

Decreases bladder activity

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53
Q

Atropine

A

Non-selective muscarinic receptor antagonist

Used to dilate eyes (mydriasis)

Bronchodilation

Decreases GI motility

Increased HR

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54
Q

Hyoscine (Scopolamine)

A

Non-selective muscarinic receptor antagonist

Used to dilate eyes (mydriasis)

Bronchodilation

Decreases GI motility

Increased HR

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55
Q

Ipatropium?

A

Muscarinic receptor antagonist used in asthma inhalers

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56
Q

What is a difference between the structures of AChE and BuChE?

A

AChE has an anionic and esteratic site

BuChE only has an esteratic site

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57
Q

How are the anticholinesterase agents classified?

A

According to length of action:-
Short acting
Medium acting
Long acting

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58
Q

Edrophonium

A

Short acting AChE inhibitor

Used to diagnose myesthenia gravis

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59
Q

Neostigmine

A

Medium acting AChE inhibitor
Binds to esteratic site and carbamoylates the enzyme

Used to reverse NMJ blockade after surgery and as an oral treatment to myasthenia gravis (prevent diminishing response)

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60
Q

Physostigmine

A

Medium acting AChE inhibitor

Glaucoma treatment

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61
Q

Malathion?

A

Long acting (irreversible) AChE antagonist

^ Parasympathetic activity

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62
Q

Dyflos?

A

Long acting (irreversible) AChE antagonist

^ Parasympathetic activity

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63
Q

Pralidoxime?

A

Causes the dissociation of dyflos/malathion from AChE to prevent poisoning

Draw the mechanism bitch

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64
Q

What is the pathway for the synthesis of Adr?

A

Tyrosine
Tyrosine hydroxylase (TOH)
DOPA
DOPA decarboxylase (DDC)
Dopamine
Dopamine β-hydroxylase (DBH)
NA
PNMT
Adr

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65
Q

At what point does the synthesis of Adr move from the cytoplasm to the vacuole?

A

Dopamine is taken in before being converted to NA

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66
Q

α-methyltyrosine

A

Competitive inhibitor of TOH

rate limiting step therefore reduces the amount of transmitter

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67
Q

L-DOPA

A

By-passes the rate limiting step of DA production

Increased DA production in the brain
(DA can’t be supplemented as it doesnt cross the BBB)

Used in the treatment of parkinsons

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68
Q

Carbidopa

A

Peripheral decarboxylase inhibitor

Inhibits DDC but cannot enter the brain = reduced side effects of L-DOPA

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69
Q

Disulfiram?

A

Inhibits DBH

Clinical used as an inhibitor of aldehyde dehydrogenase

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70
Q

MethylDOPA

A

Released as a false transmitter (MethylNA) for Adr

Greater effect on α2 receptors than NA = increased negative feedback

71
Q

How are NA and DA transported into the vesicles?

A

Transported by VMAT-2, driven by the proton gradient (established by ATP-dependent H+ pump)

72
Q

Reserpine?

A

Binds to amine binding site of VMAT
=blocks uptake

Antihypertensive
(triggers depression due to CNS -HT depletion)

73
Q

Tyramine

A

Indirectly acting sympatheticomimetic amine

Displaces NA in storage vesicles, NA then transported into synaptic cleft by NET (in exchange for tyramine)

Broken down by MAO

74
Q

What are the side effects of tyramine?

A

Large release of NA = large increase in BP

Use of MAO inhibitors increases risk

75
Q

Octopamine

A

Adr false transmitter

From tyramine

76
Q

Ephedrine

A

Indirectly acting sympatheticomimetic agent

Used in nasal sprays

77
Q

Dexamfetamine

A

Indirectly acting sympatheticomimetic agent

78
Q

Methylphenidate

A

(Ritalin)
Indirectly acting sympatheticomimetic agent

Used to treat ADHD

79
Q

MDMA

A

Indirectly acting sympatheticomimetic agent

80
Q

Tachyphylaxis

A

Reduction in effectiveness upon repeated administration

81
Q

Guanethidine

A

Blocks the release of NA

Carried into nerve by Uptake 1

Large dose: Indirectly acting sympatheticomimetic amine
Low dose: Blocks NA release (hyperpolarisation of nerve terminal)

82
Q

Bretylium

A

Blocks the release of NA

Carried into nerve by Uptake 1

Large dose: Indirectly acting sympatheticomimetic amine
Low dose: Blocks NA release (hyperpolarisation of nerve terminal)

83
Q

How do presynaptic Adr receptors work?

A

Opening of G protein regulated K+ channel = hyperpolarisation

84
Q

What effect do M2 and δ-opioid receptors have on NA release?

A

They decrease it

85
Q

What are the features of Uptake 1?

A

High affinity, low capacity
NA > Adr

Mediated by NET

86
Q

Cocaine?

A

Blocks Adr transportation by NET

87
Q

Imipramine?

A

Tricyclic antidepressant

Blocks Adr uptake by NET

88
Q

Amitryptyline?

A

Tricyclic antidepressant

Blocks Adr uptake by NET

89
Q

What is NET?

A

Catecholamine transporter

12 TM domains
Na+ dependent

90
Q

What are the features of Uptake 2?

A

Low affinity, high capacity
Adr > NA
Carried by ENT (not Na+ dependent)

Also transports DA, 5-HT and histamine

91
Q

Normetanephrine

A

Block Uptake 2 by blocking ENT

metabolite of NA therefore NA uses uptake 1

92
Q

Corticosterone and hydrocortisone

A

Block ENT

93
Q

What is the role of MAO?

A

It deamines NA or NM

94
Q

What is the role of COMT?

A

It methylates catechol OH

either NA, NA aldehyde, DOMA or DOPEG

95
Q

Where is MAO-A found? and what are its substrates?

A

In the outer mitochondiral membrane

In the liver, GI, brain and peripheral nerves

NA, Adr, DA and 5-HT

96
Q

Where is MAO-B found? and what are its substrates?

A

In the outer mitochondrial membrane in the brain

DA

97
Q

Tranylcypromine

A

Nonselective MAO inhibitor

Cause depression

98
Q

Clorgiline

A

MAO-A inhibitor

Causes depression

99
Q

Selegine

A

MAO-B inhibitor

Used as a treatment for Parkinson’s disease

100
Q

Entacapone

A

COMT inhibitor used in Parkinson’s disease

101
Q

What are the relative affinities of adrenoceptors for their substrates?

A

α- Na > Adr > isoprenaline

β- isoprenaline > Adr > NA

102
Q

How does the α1 adrenoceptor signal?

A

Gq

PLCs action cause Ca2+ release (via IP3) and activation of PKC (via DAG)

103
Q

What are the principal effects of α1 activation?

A 
Vasoconstriction (Ca2+)
Uterine smooth muscle constriction
GI smooth muscle relaxation (^I[K(Ca)])
Salivary secretion
Glycogenolysis (PKC)
104
Q

What is the mechanism of α2 signalling?

A

Gi

Gα decreases [cAMP] which in turn deactivated PKA
This inhibits VGCC activity

Gβγ also inhibits VGCC activity

105
Q

What are the principal effects of α2 activation?

A

Inhibition of transmission
Platelet aggregation
Vasoconstriction

106
Q

What is the mechanism of β1 signalling?

A

Gs

Increase in [cAMP] causing increased VGCC activity (via PKA)

Also inactivation of myosin light chain kinase (via PKA)

107
Q

What is the mechanism for β2 signalling?

A

Gs

Increase in [cAMP] causing increased VGCC activity (via PKA)

Also inactivation of myosin light chain kinase (via PKA)

108
Q

What is the mechanism for β3 signalling?

A

Gi

Decrease in [cAMP] causing a decrease in PKA activity

Increase in NO

109
Q

What are the principle effects of β1 activation?

A

Positive chronotropic and ionotropic effects

Relaxation of smooth muscle

110
Q

What are the principal effects of β2 activation?

A
  • Bronchodilation
  • Vasodilation
  • Glycogenolysis
  • Relaxation of smooth muscle in the uterus
  • Muscle tremor
111
Q

What are the principal effects of β3 stimulation?

A

Negative chronotropic and ionotropic effects

Vasodilation

Relaxation of detrusor muscle in the bladder

112
Q

What are the actions of Adr on BP, HR and TPR, and how are they mediated?

A

Decrease in TPR via α1 and β2

Increase in HR via β1

Increase in systolic and decrease in diastolic pressures

113
Q

What are the actionf of NA on BP, HR and TPR, and how are they mediated?

A

Increase in TPR
Increase in BP
Reflex decrease in HR

All via α1

114
Q

What are the actions of isoprenaline on BP, HR and TRP, and how are the mediated?

A

Increase in HR (β1)
Decrease in TPR (β2)
Increase in systolic and decrease in diastolic

115
Q

Adrenaline?

A

Used in severe acute conditions

Relieves bronchospam in anaphylactic shock (and vasoconstriction)
Stimulates heart in acute cardiac failure

116
Q

Xylometazoline

A

α-adrenoceptor agonist

Relieves nasal congestion

117
Q

Pheylephrine

A

Selective α1-receptor agonist

Increase BP in acute hypotension

118
Q

Clonidine

A

α agonist with some selectivity for α2

Antihypertensive (vasodilation)
Vasoconstriction if applied to the periphery (shaving cream)
Acts on hind brain (likely to be via the imidazoline I1 receptor)

119
Q

Xylazine

A

α agonist selective for α2

Sedative effects
Action on CNS

120
Q

Isoprenaline

A

Non selective β agonist

Bronchodilation but increased risk of dysrhythmia

121
Q

Salbutamol/terbutaline

A

β2-selective agonist

Relieves bronchospasm in asthma

122
Q

Salmeterol

A

Long acting β2-selective agonist

123
Q

Dobutamine

A

β1-selective agonist

Cardiogenic shock or to improve outflow after cardiac surgery

124
Q

Mirabegron

A

β3-selective agonist

Increases bladder capacity by relaxing detrusor muscle

125
Q

Phentolamine

A

Non selective α antagonist

Usually associated with increased HR

126
Q

Prazosin

A

α1 selective antagonist

Antihypertensive agent

127
Q

Phenoxybenzamine

A

Irreversible antagonist

Used to treat phaeochromocytoma

128
Q

Labetalol

A

α and β antagonist

129
Q

Propranolol

A

β antagonist nonselective

Class IB antidysrhythmic agent

130
Q

Atenolol

A

β antagonist (β1 selective)

Reduced risk of broncospasm

Class IB antidysrhythmic agent

131
Q

Ergotamine

A

Partial α-adrenoceptor agonist

Mainly act at 5-HT receptors

132
Q

What is ergotism?

A

AKA St Anthony’s fire

Intense vasoconstriction cause by eating fungus from mouldy grain

133
Q

What are the four main ways that drugs can affect noradrenaline release?

A
  1. Directly blocking release
  2. By evoking release in the absence of depolarisation (Indirectly acting sympatheticomimetic agents)
  3. By acting on presynaptic receptors that indirectly inhibit or enhance release
  4. By increasing or decreasing the available stores of NA
134
Q

What is NANC transmission?

A

Non-adrenergic non-cholinergic transmission

Often involves co transmission

135
Q

Is ATP stored in the same or different vesicles to NA?

A

Same vesicles

136
Q

Are peptides stored in different or the same vesicles to ACh?

A

Different

137
Q

Who discovered ATPs action as a neurotransmitter?

A

Drury & Szent-Gyorgy discovered that ATP and other adenine derivatives acted on cells of the heart

Burnstock found that ATP satisfied Dale’s criteria for a neurotransmitter

138
Q

What are the two main types of purinoceptor? and how are they distinguished?

A

P1 - Higher affinity for adenosine

P2 - Higher affinity for ATP

139
Q

What are the subtypes of the purinoceptors? and what kind of receptor are they?

A

P2X (1-7) - Ionotropic
P2Y - GPCR

P1A1 - GPCR
P1A2A - GPCR
P1AB - GPCR
P1A3 - GPCR

140
Q

What happens as ATP release by a nerve is degraded?

A

ADP etc. act upon different receptors = different responses

141
Q

What enzyme degrade ATP and where are they found?

A

Ecto-nucleotidases are found on the cell surface and nucleotidases can be co released with ATP

142
Q

What is the structure of the P2X purinoceptor?

A

Formed as a trimer of subunits (Homo or hetero)

Two TM domains
Large extracellular domain with disulphide bonds

143
Q

What is the difference in effects between ATP and NA on the postsynaptic membrane?

A 
ATP = Fast depolarisation
NA = Slow depolarisation
144
Q

What is the role of P2X2 receptors?

A

Nerve induced contraction of the vas deferens

145
Q

What is the role of P2X4 receptors?

A

ATP - ^ Force of contraction

Up-regulation in the spinal cord - tactile allodynia

146
Q

What is the main role of adenosine?

A

To signal hypoxic conditions (retaliatory metabolite)

Causes vasodilation in smooth muscle and endothelial cells

Causes a decreased rate and force of contraction of the heart (reduces O2 demand)

147
Q

What are the signalling mechanisms and principle actions of the A1 receptor?

A

Gi

Decreased HR & force of contraction
Bronchoconstriction
Presynaptic inhibition of transmitter release
Decreased brain glutamate release

148
Q

What are the signalling mechanisms and principle actions of the A2A receptor?

A

Gs

Vasodilation
Decreased activation of neutrophils

149
Q

What are the signalling mechanisms and principle actions of the A
2B receptor?

A

Gs

Vasodilation

150
Q

What are the signalling mechanisms and principle actions of the A3 receptor?

A

Gi/Gq

Decreased eosinophil activation in the lungs

151
Q

Caffeine

A

A1 receptor antagonist

Also a PDE inhibitor

152
Q

How is adenosine transmission inactivated?

A

By transport into cells

153
Q

Dipyramidamole

A

Blocks uptake and potentiates responses to adenosine

154
Q

What are the features of peptide NANC transmission?

A

Requires sustained increase in [Ca2+]i for release as peptides-containing vesicles are not found in the active zone

Slowly inactivated

Produce the late slow epsp

155
Q

What is the synthesis order of a signalling peptide?

A

Preprohormone

Prohormone

Active molecule

(one precursor can generate several active molecules)

156
Q

Why do peptides not make very good drugs?

A

Poorly absorbed orally

Rapidly degraded

Dont cross the BBB

157
Q

Oxytocin

A

Peptide drug used to induce labour

158
Q

How is NO produced?

A

Made by Ca2+ dependent enzyme nNOS and eNOS

or in a Ca2+ independent manner by iNOS

159
Q

What is the equation for the production of NO?

A

L-Arginine + O2 + NADPH -> NO + L-citrulline + NADP+

160
Q

How does NO function as a signalling molecule?

A

Freely diffuses in all directions

Activates GC in pre and postjunctional cells

PKG causes effect (eg vasodilation)

161
Q

Glyceryl trinitrate

A

NO donor used to treat angina

Taken sublingually

162
Q

Isosorbide dinitrate

A

Metabolised to isosorbide mononitrate (active)

Acts as an NO donor used in the treatment of angina

163
Q

How is NO inactivated?

A

By binding to haemoglobin or by oxidation to NO2- + NO3-

164
Q

What is the role of NO in the enteric nervous system? Which type of NOS is used?

A

ENS neurons express nNOS

Relax the pyloric sphincter

165
Q

How is penile erection mediated?

A

Release of NO by NANC nerves

=dilation of vessels supplying the corpus spongiosum and cavernosum

166
Q

Sildenafil

A

Selective inhibitor of PDE 5 used to treat impotence

Selectively breaks down cyclic GMP = potentiates NO signallin

167
Q

What is the role of NO in the CNS?

A

Acts as a retrograde messenger upon activation of NMDA-Rs

168
Q

How is NO used by the immune system?

A

iNOS in macrophages
-NO attacks Fe-S complexes = free Fe = cytotoxicity

(excess production is damaging)

169
Q

How is NO involved in septic shock?

A

Excess NO production = vasodilation and decrease in BP

170
Q

How is NO cytotoxic in the CNS?

A

Hypoxia = ^ glutamate release

= massive influx of Ca2+ = ^ NO production and cell death

171
Q

L-NMMA

A

No inhibitor

Analogue of L-Arginine

172
Q

L-NAME

A

No inhibitor

Analogue of L-Arginine

173
Q

L-NOARG

A

No inhibitor

Analogue of L-Arginine

174
Q

7-NI

A

Selectively inhibits the NOS of neurons

175
Q

L-NIO

A

A potent and irreversible inhibitor of iNOS

Shipmanising patients not clinical

176
Q

ADMA

A

Asymmetric dimethyl arginine

Endogenous NOSI

Synthesised in post-translational protein methylation

Elevated ADMA = poor prognosis

MODA (8 decks)

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