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Easter revision 2018 > ICPP > Flashcards

ICPP Flashcards

1
Q

Name an amine hormone

A

NA, adrenaline, dopamine, 5-HT

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2
Q

Out of amine, peptide and steroid hormones, order how long their half lives are

A

Amine seconds, peptide minutes, steroids hours

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3
Q

Name an amino acid neuroT

A

Glutamate, glycine, GABA

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4
Q

What are metabotropic receptors?

A

GPCRs

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5
Q

How do ionotropic Rs carry out their effects?

A

Ca2+ coupled

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6
Q

Name the alpha protein and effector molecules involved in GPCRs

A 
a1 Gaq activ PLC --> IP3 and DAG
a2 Gai inhib AC --> cAMP --> PKA
B Gas activ AC --> cAMP --> PKA
M1/3 Gaq activ PLC --> IP3 and DAG
M2/4 Gai inhib AC --> cAMP --> PKA
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7
Q

Describe the structure of a GPCR

A

7TM, single polypeptide, N terminus is extracellular and C terminus intracellular

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8
Q

What happens following PLC activation

A

Has two effectors, IP3 and DAG. IP3 joins to IP3 receptor on SR/ER which causes calcium release. DAG activates PKC which phosphorylates proteins

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9
Q

What happens following AC activation

A

AC hydrolyses ATP to create cyclic AMP which then activates PKA which phosphorylates proteins

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10
Q

At what stage is there signal amplification in GPCR signalling

A

AC activates many molecules of cAMP
PKA phosphorylates many proteins
PLC activates two effectors (IP3 and DAG)
DAG phosphorylates many proteins

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11
Q

Name all the calcium transporters/channels in a cell

A

Plasma membrane: NCX, PMCA Ca out, NOCC Ca in, LGIC Ca in

SR/ER: IP3 Ca out, SERCA Ca in, CICR (ryanodine Rs) Ca out

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12
Q

Which molecules can pass through the lipid bilayer?

A

Small uncharged polar or any hydrophobic molecules

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13
Q

What determines rate of passive transport?

A

Permeability coefficient and concentration gradients on each side J=P(C1-C2)

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14
Q

If ∆G is positive, what does this mean about the transport process?

A

Its active transport! ∆G negative is passive transport

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15
Q

What determines if it will be active or passive transport?

A

Dependent on concentration ratio and membrane potential

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16
Q

What are the glucose and fructose transporters for both sides?

A

Glucose SGLT, fructose GLUT5 and then both GLUT2 on basolateral side

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17
Q

Give an example of an ATPase Calcium transporter

A

PMCA (transports Ca out of cell)

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18
Q

What type of transporter is SGLT?

A

Cotransporter/symtransporter. Transports Na and glucose into cell

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19
Q

What is mainly responsible for RMP of -70mV?

A

Passive K+ diffusion out of cell through K+ channels

NOT Na/KATPase, this is only responsible for 5-10mV

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20
Q

Name two antiports

A

NCX (NaCa), NHE (Na H)

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21
Q

How does NaKATPase drive secondary active transport?

A

Drives Na out so provides energy for transporters that bring Na in e.g. Na/H or Na/Ca antiports or Na/glucose Na/aa symport

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22
Q

Name primary active, secondary active and facilitated transporters in Calcium

A

Primary active: PMCA (Na/CaATPase), SERCA
Secondary active: NCX
Facilitated: mitochondrial Ca uniports at high Ca to buffer harmful effects

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23
Q

What is NCX?

A

3 Na in, one Ca out (can reverse mode of operation if low Ca or high Na

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24
Q

Why do you get reversal of NCX activity in ischemia?

A

So normally NCX moves 3Na in and 1Ca out, but if ischaemic then NaCaATPase (PMCA) doesn’t work so then Na accumulates in cell so NCX reverses direction

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25
Q

What transporters control cell pH

A

NHE (Na in H out antiport), AE (HCO3- out, Cl- in)

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26
Q

What do you need to have a membrane potential?

A

Ion gradients and selective ion channels

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27
Q

What is the nernst equation?

A

Gives the equilibrium potential for an ion (=where chemical and electrical charges are balance) i.e. the membrane potential where the ion will be in equilibrium

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28
Q

If you increase membrane permeability, you move it closer/further away from its equilibrium potential?

A

Closer to its equilibrium potential

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29
Q

What is fast synaptic transmission?

A

Where the R is also an ion channel e.g. Nictonic ACh R that lets sodium in

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30
Q

What are excitatory and inhibitory synapses?

A

Ligand-gated ion channels

Excitatory causes EPSP (ACh, glutamate, dopamine) and inhibitory cause IPSP (glycine, GABA)

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31
Q

Give examples of slow synaptic transmission

A

GPCRs, use of intracellular messengers

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32
Q

How can you measure the RMP of a cell?

A

With a microelectrode

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33
Q

Where does depolarisation initiate an ap?

A

The axon hillock

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34
Q

What are the ARP and RRP?

A

Absolute refractory period- another AP cannot be generated as nearly all Na channels are in the inactivated state (they have already let Na in and now are tired)
Relative refractory period- a strong stimulus may generate an AP, Na channels recover from inactivation and less are inactivated

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35
Q

What is the structure of voltage gated Na channel?

A

Channel is made of one alpha subunit. Has four domains (I,II,III,IV) each with 6 transmembrane alpha helices. The S4 segments in each domain act as a voltage sensory- they are positively charged and following depolarisation initiate a conformational change in the channel and cause the pore to open. The pore is between S5 and S6.

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36
Q

What is the structure of voltage gated K channels?

A

Similar to voltage gated Na channels except the K channel has 4 alpha subunits. Same as Na channel with S4 voltage sensor and pore between S5 and S6.

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37
Q

How do local anaesthetics such as procaine work?

A

Block Na channels

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38
Q

In terms of axons, what order do local anaesthetics block them?

A

1st small myelinated
2nd unmyelinated
3rd large myelinated

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39
Q

What fibres conduct sharp localised pain?

A

Ad

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40
Q

What fibres conduct diffuse pain? (as well as itch)

A

C fibres

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41
Q

What theory describes the spread of charge along the axon and causes propagation of the action potential?

A

Local currents

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42
Q

What is capacitance and what is it a property of?

A

Ability to store charge, a property of the lipid bilayer

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43
Q

What is membrane resistance?

A

Relates to the number of open ion channels (high resistance = lots of ion channels closed)

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44
Q

Would would a high capacitance membrane mean for conduction?

A

Stores lots of charge so membrane charge changes more slowly

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45
Q

What would a high resistance membrane mean for conduction?

A

Lots of ion channels closed so change in voltage will spread further along the axon

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46
Q

Describe the structure of the myelin sheath

A

Schwann cell rotates around the axon to make a spiral. It is high resistance so allows current to spread further. Decreases membrane capacitance

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47
Q

What do nodes of ranvier have high concentrations of?

A

Na channels

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48
Q

What is saltatory conduction?

A

Conduction of an action potential via action potentials only occuring at nodes of ranvier then “jumping” to the next node due to the myelin sheath (which is high resistance so ap can spread)

49
Q

Name a demyelinating disease

A

Multiple sclerosis (stops saltatory conduction)

50
Q

Myelinated axons have a low/high resistance and a low/high capacitance?

A

High resistance, low capacitance

51
Q

What channels are involved in the NMJ

A

depolarisation triggers opening of Ca channels which trigger neuroT release, ACh binds to nAChR on end plate and causes voltage gated Na influx, this depolarises muscle fibre which then contracts

52
Q

Does the frequency of APs change amount of Ca entry and neuroT release?

A

Yes, higher frequency APs = more Ca entry = more neuroT release

53
Q

Describe the structure of voltage gated Ca channels?

A

Very similar to Na with 4 domains in a subunit (I,II,III,IV)

54
Q

Which subunit of Na and Ca voltage gated channels forms the pore?

A

Alpha subunit

55
Q

Which activates faster: Na or Ca voltage-gated channels?

A

Na much faster, Ca are slow

56
Q

What breaks down ACh?

A

Acetycholine esterase

57
Q

How does Ca entry lead to neuroT release?

A

Enters, binds to vesicle via synaptotagmin, vesicle moves close to membrane, Snare complex makes a fusion pore, neuroT released through pore

58
Q

What ions does nAChR let through?

A

Cations, N+ and K+

59
Q

What is an end plate potential?

A

Axon action potential –> neuroT release –> depolarisation of motor end plate occurs. This is the end plate potential –> generates action potential in the muscle

60
Q

Name a disease involving the NMJ

A

Myasthenia gravis- autoimmune against nAChRs causing profound weakness because end plate potentials are reduced

61
Q

Why are nAChRs fast acting?

A

Ligand gated ion channel (unlike GPCRs which have to trigger events)

62
Q

What are Bmax and Kd?

A

Bmax is maximum binding capacity and Kd is the drug concentration at 50% of Bmax

63
Q

Low Kd = ___ affinity

A

High affinity

64
Q

What are Emax and EC50?

A

Emax is maximal response and EC50 is concentration at 50% response i.e. EC50 is potency

65
Q

What is potency?

A

Measured by EC50, amount of response generated and depends on affinity and intrinsic efficacy (ability to activate receptor). Receptor number can change potency

66
Q

If Kd for salbutamol is 20uM for B1 and 1uM for B2, what does this mean?

A

A bit more selective for B2 than B1 (because B2 Kd is lower = higher affinity)

67
Q

Potency = ___ + ____

A

affinity + efficacy

68
Q

Why do we have spare Rs?

A 
Amplify signal transduction 
Increase sensitivity (allow responses at low concs of agonist)
69
Q

What’s the point in partial agonists?

A

Can function as antagonists in presence of full agonist, can allow a more controlled response, can work in the absence/low presence of ligand

70
Q

What is IC50?

A

Concentration of antagonist giving 50% inhibition

71
Q

Define pharmacodynamics and kinetics

A

PD- what the drug does to the body

PK- what the body does to drug

72
Q

What are enteral and parenteral drug routes?

A

Enteral is via GI (sublingual, rectal, oral)

Parenteral is via anything else (SC,IM,IT,IV)

73
Q

What are SLCs and what types are there?

A

SoLute Carriers for charged molecules across GI epithelium for drug absorption. Types are OATs or OCTs. Transport either by facilitated diffusion or secondary active transport

74
Q

Give factors affecting each of ADME

A

Absorption: drug lipophilicity, pKa, density of SLC expression, blood flow, GI motility,
Distribution: if lipophilic will cross barriers, albumin binding
Metabolism: in Liver Phase I by CYP450 and Phase II by hepatic enzymes, induction or inhibition of CYP450 by other drugs and genetic variation
Elimination: renal function

75
Q

Which drugs can passively diffuse across GI?

A

Lipophilic, weak acids and bases

76
Q

Describe the route drugs are absorbed through once in gut

A

Gut –> hepatic portal vein –> liver –> body (or enterohepatic circulation meaning back to gut via bile duct)

77
Q

Bioavailability =

A

fraction of a defined dose that reaches a specific body compartment

78
Q

What is Vd?

A

Fluid volume needed to contain drug at the same concentration as in the plasma
Bigger d gives more penetration of the V

79
Q

Higher Vd=

A

More penetration of interstitial/intracellular fluid compartment
Bigger d = more penetration of V

80
Q

What is first pass metabolism?

A

Metabolism occuring before the drug reaches the systemic circulation i.e. first pass metabolism by GI/liver

81
Q

Phase I and II liver enzymes increase/decrease ionic charge or drugs and why?

A

Increase ionic charge to enhance renal elimination

82
Q

Give an example of a CYP genetic polymorphism?

A

CYP2DR for codeine

83
Q

What routes of elimination are there?

A

Renal is main, also lung, bile, breast milk, sweat, tears, saliva, genital secretions

84
Q

What will carry charged molecules across the PCT for renal excretion?

A

OATs and OCTs (helped by previous phase I and II metabolism that increased charge)

85
Q

What is clearance?

A

Rate of elimination of a drug from the body, made up of hepatic clearance (i.e. metabolism) and renal clearance (excretion)

86
Q

What are linear kinetics?

A

Rate of clearance is proportional to drug concentration (i.e. plenty of transporters etc). Will be linear on a log scale but curvy on a concentration scale

87
Q

What are zero order kinetics?

A

Rate of clearance reaches a limit of capacity- I have zero tolerance for this! Hyperbolic on a log scale but linear on a concentration scale

88
Q

Which type of kinetics is more likely to result in toxicity?

A

Zero order

89
Q

Most sympathetic post-ganglionic neurones are…

A

noradrenergic

90
Q

Muscarinic ACh Rs and all adrenoceptors are what type of R…?

A

GPCR

91
Q

What cells in the adrenal medulla innervated by the SNS secrete adrenaline?

A

Chromaffin cells

92
Q

Describe effects of parasympathetic ACh and the receptors involved

A

Bradycardia via M2 at SAN and AVN
Bronchoconstriction via M3 at lungs
Increased GI motility via M3
Increased sweat/saliva/lacrimal M1/M3

93
Q

Describe effects of sympathetic NA and receptors involved

A

Tachycardia via B1
Bronchodilation via B2
Vasoconstriction via a1
Pupillary dilation via a1

94
Q

What are catecholamines?

A

Adrenaline and NA

95
Q

Side effects of cholinergics i.e. increased parasympathetic activity?

A

Bradycardia, bronchoconstriction

SLUDGE: salivation, lacrimation, urination. defecation, GI upset, emesis

96
Q

Which enzymes within the presynaptic terminal metabolise NA?

A

MAO and COMT

97
Q

How many people in each stage of drug development?

A

Phase 1- 50 healthy volunteers for pharmacokinetics and safety
Phase 2- 200-400 people with target disease for pharmacology
IIa is pilot study for dose finding
IIb measures therapeutic action
Phase 3- 1000-3000 target population longer term safety data, efficacy compared with current treatment, large scale RCT

98
Q

What might happen after lead identification?

A

Lead optimisation e.g. increase potency, optimise selectivity, optimise PKs,

99
Q

When are proof of concept and proof of principle established?

A

Proof of concept is Phase I/IIa

Proof of principle is Phase IIb/III

100
Q

Four ethical principles

A

Justice, autonomy, beneficience, non-maleficience

101
Q

Describe what happens in CICR

A

Ca enters myocyte via L-type Ca channels, VOCC and/or LGIC then this Ca influx stimulates ryanodine Rs on the SR so that Ca is then released from the SR

102
Q

What is a Store Operated Channel? (SOC)

A

Pumps Ca directly into SER when low

103
Q

How does a GPCR relate to calcium release from SER/SR?

A

Gq so activates PLC which activates IP3 and DAG, IP3 binds to IP3R on SR/SER to release Ca

104
Q

What is different about calcium channels in skeletal muscle?

A

T tubule VOCCs are physically coupled to ryanodine Rs

105
Q

After muscle contraction how is resting Ca regained?

A

SERCA moves Ca back into stores

106
Q

What buffers excessive Ca in a cell?

A

Mitochondria

107
Q

Name the 3 calcium buffers in the cytosol, SR, and SER

A

Cytosol- calbindin
SR- calreticulin
SER- calsequestrin

108
Q

What does calmodulin do?

A

Acts a calcium sensor protein. Binds 4 Ca, changes conformation, binds PMCA and increases PMCA sensitivity to Ca x10

109
Q

Describe normal compartment fluid volumes

A

70kg human is 60% water so 42kg. 2/3 intracellular (28k) and 1/3 extracellular (14). Of the 14L, 9L is interstitial and 5L is circulating blood volume, 3L of which is plasma and 2L is RBCs.

110
Q

How does fibre diameter affect conduction velocity?

A

Bigger diameter = faster conduction
(A fibres fastest and biggest, B fibres middle, C fibres slowest and smallest). Note A and B are myelinated, C unmyelinated

111
Q

Roughly what value is the internodal distance (between nodes of ranvier)

A

100 x external diameter of fibre

112
Q

What cells form the myelin sheath in the CNS and PNS?

A

CNS: oligodendrocytes
PNS: Schwann cells

113
Q

When does myelination occur in development?

A

Third trimester and first two ish years of life

114
Q

How does adrenaline increase inotropy?

A

Binds to Gas, cAMP and then PKA activated, PKA activates VOCC channels to increase intracellular calcium

115
Q

Equation for oral bioavailability?

A

F = AUCoral / AUCiV

116
Q

Bioavailability =

A

amount reaching systemic circulation / amount administered

117
Q

Anticholinergic side effects

A

Constipation, dry mouth, urinary retention

118
Q

What’s thyrotoxicosis? + signs/symptoms

A

Excess thyroid hormones

Tachycardia, diarrhoea, weight loss, heat intolerance, sweating, amennorhea, palmar erythema

119
Q

Name a treatment for hyperthyroidism

A

Carbimazole- inhibits thyroid peroxidase from iodinating tyrosine residues on thyroglobulin so prevents production of T3 and T4

Easter revision 2018 (11 decks)

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