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ESA 2 - RJS > M&R > Flashcards

M&R Flashcards

0
Q

What are the predominant lipids?

A

Phospholipids

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1
Q

What is the composition of a membrane?

A 
Dry weight :
60% protein
40% lipid
1-10% carbohydrate 
\+ 20% water
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2
Q

Describe the structure of a phospholipid

A

Glycerol backbone with 2 fatty acid chains and a phosphate connected to the head group

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3
Q

What are the head groups employed in phospholipids?

A

Cholines, amines, amino acids, sugars

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4
Q

Describe the structure of the fatty acid employed in phospholipids

A

C16-C18 most prevalent

Unsaturated (double bonds) in cis formation - introduces a kink

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5
Q

What does the kink in fatty acids of phospholipids achieve?

A

Reduces phospholipid packing

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6
Q

What is a cerebroside?

A

Sugar containing lipids where head group is a sugar monomer

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7
Q

What is a gangliosides?

A

Sugar containing lipids with a head group of sugar oligosaccharides

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8
Q

What two structures do amiphipathic molecules form?

A

Micelles - round droplets

Bilayers

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9
Q

How is a bilayer formed?

A

Spontaneous in water and driven by van der Walls forces between hydrophobic tails

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10
Q

How is the bilayer structure stabilised?

A

Non-covalent forces - electrostatic and hydrogen bonding between hydrophilic moieties and interactions between hydrophilic groups and water

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11
Q

How can lipid molecules move in lipid bilayers?

A

Intrachain motion
Rotation
Lateral diffusion
Flip flop

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12
Q

What are the three motions of membrane proteins?

A

Conformational change
Rotational
Lateral
Do not flip-flop

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13
Q

What are the restrictions on membrane protein mobility?

A

Aggregates
Tethering (intracellular and extracellular
Interactions with other cells

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15
Q

What are peripheral membrane proteins?

A

Proteins bound to the surface of membrane by electrostatic and hydrogen bonds

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16
Q

What does the influence of a cis bond within a phospholipid have in bilayer structure?

A

Reduces phospholipid packing

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17
Q

Describe the effects of cholesterol on the phospholipid bilayer

A

Reduces phospholipid packing therefore increasing fluidity

Rigid ring structure restricts motion of fatty acid tail which reduces phospholipid bilayer fluidity

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18
Q

What are integral membrane proteins?

A

Alpha-helical transmembrane domain of largely hydrophobic amino acids
Cannot be removed by manipulation of pH and ionic strength
Removed by agents that compete for non-polar interactions

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19
Q

Describe the erthrocyte cytoskeleton

A

Actin-spectrum network attached to membrane via ankyrin and band 4.1 bound to membrane proteins band 3 and glycophorin A respectively.

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20
Q

What is hereditary spherocytosis?

A

Spectrin depleted by 40-50% causes erythroycytes to round up and become less resistant to lysis by shearing forces of capillary beds. Cleared by the spleen

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21
Q

What molecules can diffuse the membrane bilayer?

A

Small - O2, CO2, N2, benzene

Small uncharged polar molecules - H20, urea, glycerol

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22
Q

What is passive diffusion?

A

Diffusion of molecules across a membrane either directly through the membrane or via open pores in the membrane
Dependent on permeability of membrane and concentration gradients

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23
Q

What is facilitated diffusion?

A

Gated pore, specific protein in the bilayer - ping pong transport

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24
Q

What is active transport?

A

Movement of ions or molecules againts an unfavourable concentration gradient and/or electrical gradient
Requires energy from the hydrolysis of ATP

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25
Q

What is a uniport transporter and give an example?

A

Transports an individual ion/molecule across a membrane

E.g. Voltage gated K+ channel

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26
Q

What is a symport transporter and give an example?

A

Co-transport of an ion/molecule with another across a membrane
E.g. Na+/Glucose Co-transport (Entry of Na+ provides energy for the entry of glucose against the concentration gradient)

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27
Q

What is an antiport transporter and give an example?

A

Transport of two ions/molecules across a membrane

E.g. Na+/K+ ATPase

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28
Q

What is the role of the Na+/K+ ATPase transporter?

A

Forms slight Na+ and K+ gradients using ATP

Drives secondary active transport

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29
Q

What are the secondary active transport process that Na+/K+ ATPase drives?

A 
Control of pH
Regulation of cell volume
Regulation of Ca2+ concetration
Absorption of Na+ in epithelia
Nutrient uptake, e.g. glucose from the small intestine
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30
Q

What are the intra- and extra-cellular free Na+ concentrations?

A 
Intracellular = 12mM
Extracellular = 145mM
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31
Q

What are the intra- and extra-cellular free K+ concentrations?

A 
Intracellular = 155mM
Extracellular = 4mM
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32
Q

What is the role of the sodium calcium exchanger? Describe its affinity and capacity

A

Utilises the Na+ gradient to expell Ca2+ from the cell
Low affinity, high capacity
Membrane potential dependent

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33
Q

What is the role of the plasma membrane ATPase (PMCA)? Describe its affinity and capacity

A

Removal of Ca2+, brings in H+ to increase electrochemical efficiency
High affinity, low capacity

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34
Q

What is the role of the sarco(endo)plasmic reticulum ATPase? Describe its affinity and capacity

A

Removal of Ca2+ into endoplasmic reticulum, with addition of H+ into cytoplasm - Creates store of Ca2+
High affinity, low capacity

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35
Q

What is the role of the sodium hydrogen (Na+/H+) exchanger?

A

Extrudes acid out of the cell, utilises Na+ gradient - Role in pH control

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36
Q

What is the role of the anion exchanger?

A

Extrudes base and brings in Cl-, electrochemically neutral

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37
Q

Which transporter can be reversed and when does this occur?

A

Sodium calcium exchanger
Depolarisation of cell causes reversal of transporter - Efflux of Ca2+ into the cell (e.g. muscle contraction)
Ischeamia

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38
Q

Describe why NCX is reversed in ischeamia

A

ATP is depleted in ischeamia
Na+/K+ pump therefore inhibited
Na+ accumulates in the cell —> depolarisation
NCX reverses —> Na+ moves out, Ca2+ moves in

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39
Q

Which transporters are involved in regulating pH?

A

Acid extruders:
Na+/H+ exchanger
Sodium bicarbonate co-transporter

Base extruders:
Anion exchanger

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40
Q

Briefly describe how the cell regulates cell volume

A

Osmotically ‘active’ ions (Na+, K+, Cl-) are transported into/out of the cell, causing water to follow

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41
Q

Which transporters are involved in regulating cell volume?

A

Na+/H+ exchanger
Sodium bicarbonate co-transporter
Anion Exchanger

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42
Q

What is the resting membrane potential for nerve cells?

A

-50mV to -75mV

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43
Q

What is the resting membrane potential for cardiac/skeletal muscle cells?

A

-80mV to -90mV

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44
Q

What is a membrane potential?

A

Electrical difference (voltage difference) across plasma membrane

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45
Q

What sets up the resting membrane potential?

A

Membrane is selectively permeable to K+, but not perfectly so some other ions can leak across

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46
Q

What is equilibrium potential?

A

When there is no net driving force, chemical gradient = electrical gradient (e.g. EK+ = -95mV)

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47
Q

What is the intracellular and extracellular concentrations of Na+?

A 
Intracellular = 10mM
Extracellular = 145mM
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48
Q

What is the intracellular and extracellular concentrations of K+?

A 
Intracellular = 160mM
Extracellular = 4.5mM
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49
Q

What is the intracellular and extracellular concentrations of Cl-?

A 
Intracellular = 3mM
Extracellular = 114mM
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50
Q

What is the intracellular and extracellular concentrations of anions?

A 
Intracellular = 167mM
Extracellular = 40mM
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51
Q

What is the Nerst equation used for?

A

Calculate the equilibrium potential for an ion

Chemical gradient = electrical gradient

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52
Q

What causes fast synaptic transmission?

A

When the receptor protein is an ion channel

It can either be an inhibitory post-synpatic potential or a excitatory post-synaptic potential

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53
Q

What is a inhibitory post-synpatic potential, which ions and neurotransmitters cause this?

A

Transmitters than open ligand-gated channels that cause hyperpolarisation
K+, Cl- (moving towards their equilibrium potential)
Transmitters: glycine, GABA

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54
Q

What is a excitatory post-synpatic potential and which ions and neurotransmitters cause this?

A

Transmitters that open ligand-gated channels that cause membrane depolarisation, making cell more likely to generate an action potential
Na+, Ca2+ (moving towards their equilibrium potential)
Transmitters: ACh, glutamate

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55
Q

What is slow-synpatic transmission?

A

When the receptor and channel are separate proteins, e.g. Direct G-protein gating or gating via intracellular messenger (GPCR –> enzyme –> signalling cascade –> intracellular messenger interacts with channel

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56
Q

What occurs during an action potential through an axon?

A 
Depolarisation to threshold
Na+ channels open
Na+ enters cell
Depolarisation
Opens K+ channels and inactivates Na+ channels
K+ efflux, Na+ influx stops
Repolarisation
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57
Q

What is the absolute refractory period?

A

Where all Na+ channels are inactivated and excitability is 0

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58
Q

What is the relative refractory period?

A

Where Na+ channels are recovering and excitability is increasing from 0 to 1

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59
Q

What are the stages that an Na+ channel undergoes?

A

Closed - Open - Inactivated - Closed (due to hyperpolarisation)

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60
Q

Describe the structure of a Na+ channel

A

1 subunit, 4 domains

Each domain has 6 transmembrane sections

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61
Q

Describe the structure of a K+ channel

A

4 subuntis, 1 domain

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62
Q

Describe saltatory conduction

A

Action potential jumps from node to node along axon, where there is a high density of Na+ channels, to increase conduction velocity. Myelin inhibits charge leakage.

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63
Q

Give a disease that affects saltatory conduction

A

Multiple sclerosis - demyelination of axons, loss of saltatory conduction

64
Q

How to local anasethetics generally work?

A

Block Na+ channels and therefore prevent depolarisation and spread of action potential along axon.

65
Q

What is the order in which local anasethetics block axons?

A

Small myelinated axons - sensory
Un-myelinated axons
Large myelinated axons - motor

66
Q

What sets up the calcium gradient in a cell?

A

Membrane impermeable to calcium
Ca2+-ATPase
Na+/Ca2+ exchanger
Ca2+ buffers

67
Q

What are the intracellular and extracellular concentrations of calcium?

A 
Intracellular = 100nM
Extracellular = 1-2mM
68
Q

Describe the features of the Ca2+-ATPase

A

High affinity, low capacity
Requires ATP
Feedback - increasing [Ca2+]i binds to calmodulin which binds to Ca2+-ATPase which moves more Ca2+ out of the cell

69
Q

Describe the features of Na+/Ca2+ exchanger

A

[Na+] driving force
Works well at resting membrane potential, not good during depolarisation
Low affinity, high capacity

70
Q

How do the Ca2+ buffers exert effect?

A

Limit diffusion by binding to Ca2+

E.g. Calbindin, calreticulin, parvalbumin

71
Q

What are the four ways in which Ca2+ moves during influx/efflux?

A

Voltage operated Ca2+ channels
Receptor operated Ca2+ channels
Rapidly releasable intracellular stores - sarcoplasmic reticulum
Non-rapidly releasable intracellular stores - mitochondria

72
Q

Describe the steps for calcium release from sarcoplasmic reticulum in GPCR-mediated signalling

A

Binding of ligand to GCPR
Gq protein binds
Dissociates to give G-alpha-q subunit which stimulates phospholipase C to catalyse PIP2 —> IP3 + DAG
IP3 acts of IP3 receptor on SR (ligand-gated ion channel)
Ca2+ then binds to ryanodine receptor to release more Ca2+ (calcium induced calcium release)

73
Q

How is calcium taken up into mitochondria?

A

When [Ca2+] high then Ca2+ taken up into mitochondria via uniporter (low affinity, high capacity)

74
Q

How is basal [Ca2+]i restored?

A

Recycling of cytosolic Ca2+

Depleted signal from SR sent to store-operated channel (SOC) to open to allow influx of Ca2+

75
Q

Describe the handling of Ca2+ by cardiac myoctyes

A

Action potential —> depolarsation —> opening of Na+ channels —> Opening of voltage-gated Ca2+ channels
Ca2+ acts on ryanodine receptors
Na+/Ca2+ exchanger reverses to pump Ca2+ in and Na+ out
Ca2+ causes contraction of muscle

During relaxation everything stops and Na+/Ca2+ returns back to normal and Ca2+ restored back in to SR

76
Q

What is a receptor?

A

Molecules that recognise a specific second molecule (ligand) in which binding brings about regulation of a cellular process

77
Q

What is a ligand?

A

Molecule that binds specifically to a receptor

78
Q

Describe the affinity of a ligand to receptor

A

High affinity due to low concentrations of ligand

79
Q

What is an acceptor?

A

Operates in the absence of ligand - ligand binding alone produces no response

80
Q

What is paracrine cell signalling?

A

Cascade of signal, local mediators

81
Q

What is endocrine cell signalling?

A

Between tissues transported in the blood, hormones

82
Q

What is synaptic cell signalling?

A

Between nerve cells, neurotransmitter

83
Q

What are the 4 methods of signal transduction?

A
  1. Membrane-bound receptors with integral ion channels
  2. Membrane-bound receptors with integral enzyme activity
  3. Membrane-bound receptors that signal through transducing proteins (G-proteins)
  4. Intracellular receptors - ligands pass through membrane (hydrophobic)
84
Q

Give an example of a membrane-bound receptors with integral ion channel

A

Nicotinic acetylcholine receptor - pentameric subunit arrangement, ACh binds to the 2 alpha subunits

85
Q

Give an example of a membrane-bound receptors with integral enzyme activity

A

Tyrosine kinase-linked receptors, e.g. insulin receptor - work in pairs, agonist binding causes autophosphorylation, which can then phosphorylate either the enzyme or transducer

86
Q

Give an example of a intracellular receptor

A

Cortisol receptor, oestrogen receptor, progesterone receptor

87
Q

What is the effect of Gs proteins?

A

Activates adenylyl cyclase

88
Q

What is the effect of Gi proteins?

A

Inhibits adenylyl cyclase

89
Q

What is the effect of Gq proteins?

A

Activates phospholipase C

90
Q

What is phagocytosis?

A

Internalisation of particulate matter

91
Q

What is pinocytosis?

A

Invagination of plasma membrane to form vesicle

92
Q

What is endocytosis?

A

Selective internalisation of molecules by binding to specific cell surface receptors

93
Q

What are the 4 modes of receptor-mediated endocytotis?

A
  1. Ligand degraded, receptor recycled
  2. Ligand recycled, receptor recycled
  3. Ligand degraded, receptor degraded
  4. Ligand transported, receptor transported
94
Q

Describe the coat structure used in endocytosis

A

Triskeleton of clathrin and light chains in ratio 3:2:1
Basket like structure of hexagons and pentagons
Association of coat proteins is energy dependent, coated pit formation is spontaneous

95
Q

Give an example of ligand degraded, receptor recycled receptor-mediated endocytosis

A

Uptake of cholesterol

96
Q

Describe ligand degraded, receptor recycled receptor-mediated endocytosis with respect to cholesterol

A

LDL (ligand) binds to LDL-receptor
Coated pit formation
Coated vesicle invaginates
Uncoating of vesicle - requires ATP
Vesicles fuses with endosome (pH 6.0 due to H+-ATPase) - CURL, compartment for the uncoupling of receptor and ligand
Dissociation of ligand and receptor due to decrease in pH
Endosome fuses with lysosome, ester core hydrolysed to cholesterol to be used in the cell
LDL-receptor recycled to surface

97
Q

What are the 3 mutations that can affect LDL receptor in hypercholesterolamia?

A
  1. Receptor deficiency
  2. Non-functional receptor (no binding of LDL)
  3. Deletion at C-terminal of receptor that interacts with coated pit (receptor binding normal, no internalisation)
98
Q

Give an example of ligand recycled, receptor recycled receptor-mediated endocytosis

A

Uptake of Fe3+ by transferrin

99
Q

Describe ligand recycled, receptor recycled receptor-mediated endocytosis with respect to Fe3+ uptake

A

Apotransferrin binds 2 Fe3+ —> Ferrotransferrin
Binds to transferrin receptor
Coated pit —> invagination —> uncoating of vesicle (pH decreases due to H+-ATPase)
Fuses with endosome (CURL), pH 5.0 —> Fe3+ dissociates with apotransferrin
Fe3+ moves into the cytosol
Apotransferrin and receptor and recycled back to the surface, neutral pH causes dissociation of apotransferrin from receptor

100
Q

Give an example of ligand degraded, receptor degraded receptor-mediated endocytosis

A

Uptake of insulin

101
Q

Describe ligand degraded, receptor degraded receptor-mediated endocytosis with respect to insulin

A

Receptors only congregate over coated pit when agonist is bound —> conformational change of receptor to be recognised by coated pit
Invagination —> uncoating —> fuses with endosome (ligand & receptor remain bound)
Targeted to lysosome for degradation
Mechanism allows for down-regulation of receptors with desensitises cell to continued presence of high circulating insulin concentrations

102
Q

Give an example of ligand transported, receptor transported receptor-mediated endocyotsis

A

Uptake of immunoglobin (IgA) from circulation to bile

103
Q

Describe ligand transported, receptor transported receptor-mediated endocyotsis with respect to immunoglobin

A

Undergoes same mechanism as uptake of cholesterol however once in the endosome a vesicle pinches off with receptor and ligand (which dissociate) and heads for bile where they are removed.

104
Q

Explain how viruses and toxins enter the cell

A

Exploit endocytic pathways by binding to receptors.
Once in endosome (favourable pH), viral membrane fuses with endosomal membrane releasing viral RNA into cell for replication

105
Q

What is signal transduction?

A

Binding of ligands to receptor triggers a biochemical chain of events

106
Q

Give a medication and its method of action for decreased sodium reabsorption in the thick ascending limb

A

Loop diuretics

Inhibits the Na-K-2Cl cotransporter

107
Q

Give a medication and its method of action for decreased sodium reabsorption in the distal convoluted tubule

A

Thiazides
Inhibits Na-Cl cotransporter

Amiloride
Blocks epithelial Na channel

108
Q

Give a medication and its method of action for decreased sodium reabsorption in the cortical collecting duct

A

Amiloride

Inhibits epithelial Na channel

109
Q

Where in the kidney does aldosterone exert its action

A

Cortical collecting duct

110
Q

What is the action of aldosterone in the kidney?

A

Stimulates increased Na uptake and therefore H2O retention causing increased blood pressure

111
Q

What occurs during accommodation?

A

The longer the stimulus the larger the depolarisation necessary to initiate an action potential - threshold becomes more positive
Increasing numbers of Na channels become inactivated

112
Q

How does neurotransmitter release occur at neuromuscular junction?

A

Depolarisation open voltage-operated Ca2+ channels
Ca2+ binds to synaptotagmin
Brings vesicle close to membrane
Binds to snare complex to make fusion pore
Release of neurotransmitter into synaptic cleft through pore
ACh acts on nAChR on post-synaptic membrane
Open voltage-gated Na+ channels

113
Q

What are the 2 types of nAChR blockers and give examples?

A

Competitive blockers - tubocurarine

Depolarisation blockers - succinylcholine

114
Q

What is myasthenia gravis and what does it present with?

A

Autoimmune destruction of nAChR
Profound muscle weakness
Weakness in external ocular muscles (dropping of eyelides)
Muscles fatigue more readily after exercise

115
Q

What are the 3 superfamilies of cell-surface receptors and give an example?

A

Ligand-gated ion channels - nAChR
Receptors with intrinsic enzymatic activity - tyrosine kinases
G-protein coupled receptors - mAChR

116
Q

Give an example of a disease resulting from GPCR mutation

A

Retinitis pigmentosa - loss of function, mutation to rhodopsin

117
Q

Describe the structure of G-protein coupled receptors and where binding can occur

A

7 transmembrane domains

Can occur at either transmembrane domains or N-terminal region

118
Q

How is the G-protein activated?

A

GPCR interaction with G-protein causes exchange of GDP to GTP
alpha-beta-gamme complex immediately dissociates to produce an effect

119
Q

What are the two types of effectors that can be stimulated by GPCR system?

A

Enzymes - Adenylyl cylase, phospholipase C

Ion channels - VOCC

120
Q

Explain the stimulation of adenylyl cyclase and its effect

A

G-alpha-s protein complex
GDP replacement with GTP causes dissociation
Alpha subunit acts on adenylyl cyclase to convert AMP to cAMP
cAMP then acts on PKA which phosphorylates target proteins

121
Q

Give some effects of PKA stimulation through adenylyl cylcase activation

A 
Sympathetic stimulation: Therefore must
Increase glycogenolysis & glyconeogenesis
Increase lipolysis
Relaxation of smooth muscle
\+ve chronotropic and inotropic effects
122
Q

Explain the inhibtion of adenylyl cyclase and its effect

A

G-alpha-i protein complex
GDP replacement with GTP causes dissociation
Alpha subunit inhibits adenylyl cyclase, therefore decreased amount of cAMP and decreased amounts of PKA
Decreased phosphorylation of proteins/enzymes

123
Q

Explain the stimulation of phospholipase C and its effect

A

G-alpha-q protein complex
GDP replacement with GTP causes dissociation
Alpha subunit acts on phospholipase C which catalyses PIP2 to IP3 and DAG
IP3 acts on IP3 receptor on SR to release Ca2+
DAG activates phospholipase C which inhibits myosin-light chain phosphatase (prevents removal of phosphate group from myosin light chain, continuing contraction)

124
Q

Explain contraction of smooth muscle

A

G-alpha-q protein complex - dissociates due to GDP –> GTP
Activation of phospholipase C to cause PIP2 —> IP3 + DAG
IP3 acts on IP3 receptor to increase cytostolic Ca2+
Ca2+ binds to calmodulin which then binds to myosin-light chain kinase
Then, with addition of ATP, able to phosphorylate myosin head, causing contraction

125
Q

Explain mechanism causing a -ve chronotropic effect

A

M2 receptor activated via ACh
G-alpha-i protein which inhibits adenylyl cyclase
The beta-gamma subunit acts on the K+ channels, increasingly their open probability
This causes hyperpolarisation, making it harder to reach threshold, decreasing gradient of If —> therefore having a negative chronotropic effect

126
Q

Explain the mechanism causing a +ve chronotropic effect

A

B1 receptor activated via noradrenaline
G-alpha-s activates adenylyl cyclase, increasingly cAMP
Binds to channels to increase open probability and therefore increases gradient of If

127
Q

Explain the mechanism causing +ve inotropic effect

A

B1 receptors activated via noradrenaline
G-alpha-s activates adenylyl cyclse, increasing cAMP which increases PKA
PKA phosphorylates VOCC, increasing their open probability, increasing Ca2+ influx

128
Q

Explain the mechanism causing arteriolar vasoconstriction

A

A1 receptors activated via noradrenaline
G-alpha-q activates phospholipase C, causing PIP —> IP3 + DAG
IP3 receptor activation, release of intracellular Ca2+
Ca2+ binds to calmodulin, then myosin-light chain kinase which with ATP phosphorylates myosin head

129
Q

Explain the mechanism of inhibition of neurotransmitter release

A

Mu-opiod receptors = Gi = -Adenylyl cyclase
Beta-gamma subunit interacts with VOCC, causing decrease in Ca2+ influx
Ca2+ required from vesicle fusion and release, therefore inhibits neurotransmitter release

130
Q

What is molarity?

A

Number of moles of a substance per litre of solution

131
Q

What is moles?

A

Amount of substance (number of atoms)

132
Q

What is intrinsic efficacy?

A

Ability of binding event to provoke acellular event (ability to turn on a receptor) or produce maximal functional response

133
Q

What is Kd?

A

Concentration of ligands required to occupy 50% of available receptors - measure of affinity

134
Q

What is Bmax?

A

Maximal binding capacity - receptor number

135
Q

What is EC50?

A

Effective concentration giving 50% maximal response

Measure of agonist potency (depends on both affinity and intrinsic activity, also determined by amount of receptors)

136
Q

Explain agonist in terms of affinity and intrinsic efficacy

137
Q

Explain antagonist in terms of affinity and intrinsic efficacy

A

Has affinity but no intrinsic efficacy

138
Q

What is potency?

A

A measure of drug activity expressed in terms of the amount required to produce an effect of given intensity

139
Q

What does spare receptors indicate?

A

Increased sensitivity - allows responses at lower concentration gradients
However numbers are not fixed

140
Q

What is a full agonist?

A

Produces a full response - +/- spare receptors

141
Q

What is a partial agnoist?

A

Produces a partial response - all receptors occupied

may not always be partial, receptor number could change causing it to become a full agonist

142
Q

What is functional antagonism?

A

Partial agonist can act as antagonist of full agonist - occurs when partial agonist has high affinity for receptors than full agonist

143
Q

What are the 3 mechanisms of antagonists?

A
  1. Reversible competitive antagonism - relies on dynamic equilibrium between ligands and receptors (greater antagonists conc = greater inhibition)
  2. Irreversible competitive antagonism - antagonist dissociates slowly or not at all (suppresses maximal response)
  3. Non-competitive antagonism - allosteric binding site or orthosteric site
144
Q

Name some sites of adminstration of drugs? Which are subjected to first pass effect

A 
Sub-lingual
Inhalation
Oral 
IV, IM, SC
Topical
Transdermal patch
Rectal

First pass effect - those that have to pass the liver (oral)

145
Q

What is oral bioavailability?

A

Proportion of drug given orally that reaches circulation uncharged (measured by amount and rate)
= (AUC oral / AUC injected) x 100 (of graph plasma conc vs time)

146
Q

What is therapeutic ratio and how is it calculated?

A

How safe a drug is
LD50 / ED50

LD50 = lethal dose to 50% of population
ED50 = effective dose to 50% of population
147
Q

What is drug distribution?

A

Theoretical volume which drug has distributed into, assuming it has occurred instantaneously
Amount given / plasma concentration at T=0

148
Q

What is drug distribution effected by?

A

Protein binding interactions e.g. albumin (only free drug able to exert effect)

149
Q

How is protein binding interactions overcome?

A

Object drug (class 1) used at lower dose than number of albumin binding sites, precipitant drug (class 2) used at higher dose than number of albumin binding sites - When used together class 1 drug is displaced by class 2, therefore increasing concentration of unbound class 1 drug

150
Q

What are the two routes of drug elimination

A

Metabolism in liver - oxidation & conjugation via cytochrome p450
Excretion via kidneys - only free fraction of drug is filtered (if it is an acidic drug, make urine more alkaline to increase excretion/elimination

151
Q

What is zero order kinetics? Give an example of a drug that has zero order kinetics

A

Rate of elimination is constant (plasma conc vs time)

Alcohol, warfarin, heparin, aspirin

152
Q

What is first order kinetics? Give an example of a drug that has zero order kinetics

A

Rate of elimination is proportional to drug level - half life can be defined
All other drugs

153
Q

In neurotransmitter synthesis and release which steps are targets for drugs?

A 
Degradation of transmitter
Interaction with post-synoptic receptors
Inactivation of transmitter
Re-uptake of transmitter
Interaction with pre-synaptic receptors
154
Q

What classes of drugs affect cholinergic transmission?

A

Acetylcholinesterase inhibitors - Enhances the action of ACh
mACh receptor - agonists/antagonists - Lack subtype selectivity, therefore unwanted side effects (clinically useful if used locally)

155
Q

What classes of drugs affect noradrenergic transmission?

A

Indirectly-acting sympathomimetic agents (e.g. amphetamine, ephedrine) - They are taken up into the pre-synaptic vesicle displacing noradrenaline, then leak into synaptic cleft without Ca2+-mediated exocytosis
B2-adrenoceptors selective agonists (e.g. salbutamol) - Causes bronchodilation, selectivity reduced unwanted side effects
B1-adrenoceptor-selective antagonists (e.g. atenolol) - used to treat hypertension, inhibit adenylyl cyclase
Also act on pre-synaptic alpha 2 receptors to inhibit VOCC via beta-gamma subunit

ESA 2 - RJS (6 decks)

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