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ESA 2 > M&R > Flashcards

M&R Flashcards

0
Q

Constituents of membranes

A

40% lipid, 60% protein, 1-10% carbohydrate

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1
Q

5 Function of Biological Membranes

A
  1. Continuous, highly selective permeability barrier
  2. Allows control of the enclosed chemical environment
  3. Communication - control flow of info between cells and environment
  4. Recognition - signalling molecules, adhesion proteins, immune surveillance
  5. Signal generation in response to stimuli
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2
Q

What makes up a phospholipid?

A

Glycerol, 2 fatty acids and a phosphate head

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3
Q

Examples of polar heads of a phospholipid

A

Choline, amine, AA’s

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4
Q

Effects of having a cis double bond kink in a fatty acid of a phospholipid

A

Reduces phospholipid packing, allowing fluidity

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5
Q

What are the 2 types of GLYCOLIPID?

A
  • Head group is a sugar monomer = Cerebroside

- Head group is an oligosaccharide = Ganglioside

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6
Q

4 Possible types of movement of a membrane bliayer

A

Flexion, Rotation, Lateral Diffusion, Flip-Flop (movement of lipids from one half of the bilayer to the other)

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7
Q

Properties of cholesterol

A

Rigid, planar steroid ring structure, with a polar head.

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8
Q

Effects of cholesterol on phospholipids at high and low temperature

A

High temp: reduced phospholipid chain motion: reduced fluidity.
Low temp: reduced phospholipid packing: increased fluidity.

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9
Q

What evidence is there for the presence of proteins in membranes?

A

They serve functions, e.g. facillitated diffusion, ion gradients etc. There is also biochemical evidence proven by freeze fracture of the membranes and also via SDS-PAGE of the membrane.

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10
Q

Which movements are possible for proteins in a bilayer?

A

Conformational change (e.g. opening/closure of channels), Rotation and Lateral. NO FLIP-FLOP (as energy required is too high and would disrupt the bilayer structure)

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11
Q

What are peripheral membrane proteins? How can they be removed?

A

Proteins bound to the surface by electrostatic/hydrogen bond interactions. They can be removed by pH/ionic strength change.

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12
Q

What are integral membrane proteins? How can they be removed?

A

They are proteins that interact extensively with hydrophobic domains of the lipid bilayer. They can be removed via agents that compete for non-polar interactions e.g. detergents.

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13
Q

What do hydropathy plots measure?

A

They measure the hydrophobicity of AA’s of a protein. If >1 hydrophobic region then there is >1 transmembrane domain, so the protein may fold in and out of the bilayer.

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14
Q

Topology?

A

The orientation of a protein within the bilayer. This is important as the recognition site must be facing the correct direction (intracellularly or extracellularly).

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15
Q

Erythrocyte membrane analysis

A
  • Prepare ghost membranes via osmotic haemolysis. Then analyse membrane by gel electrophoresis.
  • Peripheral proteins are removed by a salt wash. Hence these proteins must be on the cytoplasmic face as they are susceptible to proteolysis when only this face is susceptible.
  • Integral proteins are removed only via detergents.
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16
Q

Properties of the erythrocyte cytoskeleton

A
  • Composed of a network of spectrin and actin molecules.
  • alpha and beta spectrin units wind to form an alpha-2-beta-2-heterotetramer.
  • These rods are cross-linked into networks actin proto-filaments, and band 4.1 and adducin molecules form interactions towards the ends of the rods.
  • This is attached to the membrane via adapter proteins e.g. Ankyrin, ensuring restricted lateral mobility of membrane proteins.
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17
Q

What are the 2 types of haemolytic anaemias?

A
  1. Hereditary Spherocytosis - depleted spectrin, so cells round up, and are less resistant to lyse, so are cleared by the spleen.
  2. Hereditary Elliptocytosis - Spectrin defect so heterotetramers cannot form, giving fragile elliptoid cells (rugby ball shaped RBC’s)
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18
Q

What are the stages of membrane protein biosynthesis?

A
  • Translation of the protein is halted and the hydrophobic AA sequence at the N-terminus is recognised by a signal recognition particle (SRP). Binding to this is what prevents the continuation of protein synthesis.
  • The SRP is recognised by a SRP receptor (docking protein). The SRP is then released.
  • The signal sequence interacts with the signal sequence receptor (SSR which is in a protein translocator complex) in the ER membrane, directing protein synthesis to continue into the ER.
  • The stop transfer signal spans the bilayer, and this forms the transmembranous region.
  • The membrane protein is released from the protein translocator into the bilayer.
  • The N-terminal signal sequence is directed into the lumen, C-terminal sequence into the cytoplasm.
  • Signal sequence cleaved by signal peptidase.
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19
Q

Where does further post-translational processing occur?

A

ER and Golgi

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20
Q

Molecules that lipid bilayers are permeable to

A

Hydrophobic/ small uncharged polar molecules.

E.g. h2o, O2, CO2, Urea, glycerol

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21
Q

Molecules that lipid bilayers are not permeable to

A

Ions/ large uncharged polar molecules.

E.g. Glucose, H+, Na+, Ca2+, Cl- etc.

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22
Q

Properties that transport processes need to maintain include

A

Ion conc. Intracellular pH. Cell volume.

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23
Q

How do ligand-gated ion channels work?

A

Ligand binds to receptor, causing conformational change that opens the channel.

E.g. ATP-sensitive K+ channel. ATP conc. high in cell, and stops the outward flow of potassium ions from cell.

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24
Q

How do voltage-gated ion channels work?

A

Voltage sensor detects membrane depolarisation. Causing conformational change. The inside is normally more negative than the outside.

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25
Q

What two properties allow passive movement of ions across a membrane?

A

Down concentration gradient, and membrane potential in favour of movement of the ion.

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26
Q

What are the Intracellular and extracellular concentrations of Na+?

A 
Intracellular = 12mM
Extracellular = 145mM
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27
Q

What are the Intracellular and extracellular concentrations of Cl-?

A 
Intracellular = 4.2mM
Extracellular = 123mM
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28
Q

What are the Intracellular and extracellular concentrations of Ca2+?

A 
Intracellular = 0.0001mM
Extracellular = 1.5mM
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29
Q

What are the Intracellular and extracellular concentrations of K+?

A 
Intracellular = 155mM
Extracellular = 4mM
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30
Q

What are primary active transporters? Give an example.

A

They hydrolyse ATP directly to move molecules across bilayer.
E.g. PMCA Hydrolyses ATP to pump Ca2+ outside cell, against gradient.

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31
Q

What is the difference between uniport, symport and antiport?

A

Uniport transports one ion type across Bilayer at a time.
Symport cotransports two different ions together in the same direction.
Antiport cotransports two different ions together in opposite directions.

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32
Q

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

A

Hydrolyses ATP to move 3 Na+ out and 2 K+ into the cell. (An antiport - primary active transporter). This generates an inwards Na+ gradient and an outwards K+ gradient.

The alpha subunit Hydrolyses ATP and moves the ions.
The beta subunit directs the pump from ER to plasma membrane.

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33
Q

Which ion gradient is mainly responsible for the membrane potential?

A

K+

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34
Q

What is the role of the Na+ Ca2+ exchanger?

A

Uses the inward Na+ gradient to drive one Ca2+ out for every 3Na+ into the cell.

Low affinity (so only removes calcium when levels are raised), high capacity.

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35
Q

What is the role of the Na+ H+ exchanger?

A

Uses the Na+ gradient to export 1 H+ out for every Na+ into the cell. This maintains pH.

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36
Q

What is the role of the Na+ Glucose co-transporter?

A

It uses the Na+ gradient to drive glucose from gut lumen into the cell.

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37
Q

What is the role of the CFTR protein?

A

It’s a chloride transporter that transports chloride from epithelial cells outside of the cell. Drawing water with it to hydrate mucus.

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38
Q

What is the connection between protein kinase A and diarrhoea?

A

If protein kinase is activated, Cl- transport through the CFTR channel is enhanced. Drawing more water into the gut lumen,therefore causing diarrhoea.

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39
Q

Why is it important to maintain a low concentration of Ca2+ inside the cell?

A

High concentration is toxic to cells as it binds with phosphate and causes ossification of cells. Small changes are used for signalling.

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40
Q

What is the role of PMCA (Ca2+ - ATPase)?

A

Removes Ca2+ even when it’s concentration is low.

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41
Q

What is the role of SERCA (sarcoendoplasmic reticulum - ATPase)?

A

Drives Ca2+ into the ER store

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42
Q

What controls cell pH?

A

Acid Extruders.
NHE (Na+H+ exchangers) exports H+ from cell and imports Na+.
NBC (Sodium bicarbonate cotransporter) exports Cl- and imports HCO3-.

Base Extruders.
Cl-/HCO3- exchanger (AE) uses chloride gradient to drive out HCO3-.

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43
Q

What happens if pH starts to fall/increase?

A

FALL IN pH: NHE increases activity, excluding H+ ions.

INCREASE IN pH: AE activated, decreasing pH.

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44
Q

How is cell volume regulated?

A

Via transport of osmotically active ions, e.g. Na+, Cl-, K+. So that water will follow. If cell is swelling, extrude ions so that water follows. If cell is shrinking, induce an influx of ions.

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45
Q

Name two mechanisms to resist cell swelling

A

Use K+/Cl- channels.
Extrude amino acids.
K+/Cl- co-transporter to remove these ions so water will follow.

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46
Q

Describe Na+ reuptake via the thick ascending limb of the kidney

A

The Na+K+2Cl- cotransporter transports sodium, potassium and chloride ions out of the filtrate to the cell. The Na+ then enters the bloodstream via Na+K+ATPase. K+ and Cl- also enter the blood.
ROMK involve potassium channels to allow it to leak from cell to filtrate.

LOOP DIURETICS (renal hypertensive therapy) inhibit Na+K+Cl- so that Na+ is lost in the urine. Therefore water leaves blood thus reducing blood pressure.

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47
Q

How is a resting potential set up?

A

Potassium ions leave via ion channels down their concentration gradient. The anions are left behind, hence the potential is more negative on the inside of the membrane.
When the outwards chemical K+ gradient is equal to the inwards electrical K+ gradient, there will be no net movement of k+.

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48
Q

Which equation can be used to establish the membrane potential at which an ion will be in equilibrium?

A

The Nernst Equation

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49
Q

What is approximately the electrochemical equilibrium for k+?

A

-95mV

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50
Q

Give three reasons for a change in membrane potential

A

Triggering a muscle contraction
Control of hormone secretion
Transduction of sensory info into electrical activity via receptors.

51
Q

What is depolarisation?

A

A decrease in the size of the membrane potential from it’s normal value. Therefore it’s less negative.

52
Q

What is hyperpolarisation?

A

An increase in the size of the membrane potential from its normal value, therefore it’s more negative.

53
Q

What is synaptic transmission?

A

The chemical transmitter released from Presynaptic cell, that binds to receptors on the postsynaptic membrane.

54
Q

What is fast synaptic transmission?

A

The receptor protein is also the ion channel. So the transmitter binding causes the channel to open.
At excitatory synapses, the neurotransmitters open ligand-gated channels, causing depolarisation. (Na+/Ca2+)

55
Q

What is slow synaptic transmission?

A

Where the receptor and the channel are separate proteins. E.g. G-protein gating.

56
Q

What is an action potential?

A

A change in voltage across a membrane. It depends on ion gradients, and the relative permeability of the membrane. Only occurs if threshold is reached.

57
Q

Explain repolarisation

A

Na+ channels are inactivated, so they close. K+ channels open, causing a K+ efflux, as they attempt to establish their equilibrium.

58
Q

Characteristic of the absolute refractory period?

A

Nearly all Na+ are in the inactivated state.

59
Q

Characteristic of the relative refractory period?

A

Na+ channels recovering from inactivation. Excitability returns towards normal as the number of inactive channels decreases.

60
Q

What is the structure of a voltage-gated Na+ channel?

A

One peptide consisting of 4 homologous repeats. Each repeat consists of 6 transmembrane domains. One of the domains in each repeat is able to sense voltage across the membrane. A functional channel requires one subunit.

61
Q

What is the structure of a voltage-gated K+ channel?

A

4 subunits required to make a functional channel. Each repeat is a separate subunit. Each subunit still has 6 transmembrane domains, one of which is voltage sensitive. Also has a pore region which contributes to pore selectivity.

62
Q

How do local anaesthetics work?

A

E.g. Procaine. Act by binding to and blocking Na+ channels, stopping action potential generation.

63
Q

Describe the two methods used by local anaesthetics.

A

Hydrophobic pathway: local anaesthetic gets into the membrane as it is lipid soluble. It can pass through the Na+ channel and block it.

Hydrophilic pathway: goes through the membrane, becomes protonated, blocks the channels once they are open. The more channels that are open, the more that become blocked.

64
Q

Describe the local current theory of propagation

A

Depolarisation will cause the charge to spread along the axon, causing an immediate local change in the membrane potential. Opening more Na+ channels further along in neighbouring regions. The further the current spreads, the faster the conduction velocity of the axon.

65
Q

What factors affect conduction velocity?

A
  • the higher the membrane resistance, the higher the potential difference across it.
  • the larger the axon diameter, the larger the current, so increased conduction velocity.
  • low membrane capacitance gives increased conduction velocity.
66
Q

Affect of myelination on conduction velocity

A

Myelination increases conduction velocity. It reduces capacitance and increases membrane resistance.

67
Q

What is used to myelinate axons?

A

Schwann cells myelinate peripheral nerves.

Oligodendrocytes myelinate axons in the CNS.

68
Q

What are the consequences of demyelination?

A

Can lead to decreased conduction velocity, complete block or cases where only some action potentials are transmitted.

69
Q

What stimulates the release of neurotransmitters?

A

When an action potential arrives at nerve terminal, voltage gated Ca2+ channels open in response to depolarisation. This causes a Ca2+ influx, raising Intracellular [Ca2+], which stimulates the release of neurotransmitter.

70
Q

Where are L-type calcium channels found?

A

In muscle/neurones/lung

71
Q

How are neurotransmitters released?

A

Ca2+ enters via channels, which then binds to synaptotagmin proteins, which brings the vesicles closer to the membrane. The vesicles then bind with another set of proteins to form a snare complex. This then makes a fusion pore to allow the neurotransmitter to diffuse out through, into the synaptic cleft.

72
Q

What are ligand gated nicotinic ion channels?

A

Proteins with an intrinsic pore, that opens in response to a conformational change, induced via the binding of a ligand to the receptor. ACh binds, opening the channels pore.

73
Q

What is the end plate potential?

A

Change in membrane potential in response to ACh acting on nicotinic ACh receptors. Depolarising to threshold, firing an action potential in the skeletal muscle fibre. This then contracts.

74
Q

How to competitive receptor blockers work?

A

They combine with the receptor, so channel is not open and ACh cannot bind. Less depolarisation with same amount of ACh. If you increase conc. of ACh then may get to site before the blocker.

75
Q

How do depolarising receptor blockers work?

A

They activate the receptors, but aren’t broken down. This results in a slow, maintained depolarisation. This initially opens Na+ channels, however these then become inactivated, so no action potentials initiated.

76
Q

What is a miniature end-plate potential?

A

Small packets of ACh released into synaptic cleft, producing a smaller version of the end-plate potential. Hence doesn’t reach threshold.

77
Q

What is myasthenia gravis?

A

An autoimmune disease where antibodies attack nicotinic ACh receptors on post-synaptic membranes of skeletal muscle. Reducing amplitude of end plate potentials, leading to muscle weakness and fatigue.

78
Q

What is the difference in response speed between nicotinic snd muscarinic ACh receptors?

A 
nACHr= fast depolarisation as ligand-gated ion channel. 
mAChr= slower response as they are coupled to G-proteins which trigger a cascade of events within the cell.
79
Q

Give two ways that calcium is removed from cells

A

1) Ca2+ ATPase: calcium ions bind to calmodulin which activates this process, removing Ca2+ from cells. High affinity, low capacity.
2) Na+/Ca2+ exchanger: uses sodium gradient to bring 3Na+ in, and 1Ca2+ out. Low affinity, high capacity.

80
Q

How is calcium released form Intracellular stores?

A

When [Ca2+] is high in the stores, Ca2+ATPase is used to move Ca2+ against its concentration gradient from cytoplasm via SERCA pump, using ATP. Low affinity, high capacity.

81
Q

How is calcium released from stores via G-protein coupled receptors?

A

A ligand binds to the GPCR of the plasma membrane. They then undergo a conformational change, which activates a heterotrimeric G-protein (in particular, it’s alpha-q subunit). This subunit then binds to the membrane phospholipid PIP2, releasing IP3. IP3 binds to its receptor on the SER, triggering release of calcium, down conc. gradient, into cell.

82
Q

How does Ca2+ induced Ca2+ release work?

A

Ca2+ binds to Ryanodine receptor on the SER, triggering ca2+ release into the cell.

83
Q

Why would calcium be taken up by the mitochondria?

A

When [Ca2+] is too high. Also to aid in buffering, regulating, signalling, and stimulation of ATP production. This is done via a Ca2+ uniporter, driven via respiration.

84
Q

How is Intracellular [Ca2+] returned to basal levels?

A

Requires, a termination of the signal, Ca2+ removal, and Ca2+ store refilling.
Ca2+ channels are refilled by Cytosolic calcium and also that from mitochondria. Mitochondrial Ca2+ replenishes stores via store-operated Ca2+ channel.

85
Q

What are the three types of intercellular signalling?

A

Paracrine: signalling molecule secreted into interstitial space, and binds wirh adjacent cells, allowing activated cell to transmit messages to nearby cells.
Endocrine: signalling molecules released into bloodstream. These are then transmitted around circulation, where they bind to distant target tissue to generate a response.
Neuronal: neurotransmitters cross cell junctions in nervous system.

86
Q

Cell surface vs Intracellular receptors differences?

A

Cell surface: hydrophilic signalling molecule binds to cell surface, generating response inside the cell.
Intracellular: hydrophobic signalling molecules carried in the blood on a carrier protein. They can penetrate the membrane directly, without use of a receptor. They then bind to an Intracellular receptor.

87
Q

What is a receptor?

A

A molecule (that is silent at rest) that specifically recognises a ligand/family of molecules. Upon ligand binding, it brings about regulation of a cellular process.

88
Q

What are the 4 ways to transduce an extracellular hydrophilic signal into an Intracellular event?

A

1) membrane bound receptors with integral ion channels
2) membrane bound receptors with integral enzyme activity
3) membrane bound receptors which couple to effectors through transducing proteins
4) Intracellular receptors for hydrophobic Ligands

89
Q

What role does amplification play?

A

By stimulating the activity of an enzyme, the binding of a chemical signal molecule to a single receptor can cause the modification of hundreds or thousands of substrate molecules. A cascade of such catalytic events can produce further amplification.

90
Q

Describe phagocytosis

A

Particle binds to receptors in plasma membrane, cell extends pseudopods, allowing further receptor interactions and envagination. The phagosomes fuse with lysosomes and the particulate material is degraded.

91
Q

What is pinocytosis?

A

The invagination of the lipid membrane to form a lipid vesicle. Allowing the uptake of impermeable extracellular solutes.

92
Q

What is receptor mediated endocytosis?

A

Specific binding of molecules to cell surface receptors, allowing the selective uptake of substances into the cell.

93
Q

How is cholesterol uptaken?

A

Cholesterol is carried in LDLs. Cells requiring it have LDL receptors, that recognise apoprotein B. Post-binding, the LDL is internalised, and delivered to lysosomes where the cholesterol is released.
LDL receptors are in pits that pinch off to form coated vesicles. They become uncoated and fuse with endosomes.
The contents of the endosomes are passed onto lysosomes, where cholesterol is de-esterified and released into cell.

94
Q

Which 3 mutations affect LDL receptors?

A

1: receptor deficiency due to lack of LDL receptor expression.
2: non-functioning receptor hence LDLs do not bind.
3: no internalisation of LDLs due to deletion in c-terminal of receptor that makes interactions with coated pits. (Also LDL receptors located across whole cell surface).

95
Q

What is transcytosis?

A

Some Ligands stay bound to their receptor and are transported across the cell. E.g. Maternal immunoglobulins to foetus via placenta.

96
Q

How does an antagonist work?

A

Binds to receptor to block the effects of agonists. Used to treat hypertension/schizophrenia etc.

97
Q

4 properties or GPCRs

A
  • single polypeptide chains
  • 7 transmembrane spanning domains
  • an extracellular n-terminal
  • an Intracellular c-terminal
98
Q

How do GPCRs initiate a response?

A

Ligand binds to GPCR, causing a conformational change. This then attracts and interacts with a G-protein.
The G-proteins becomes activated by exchanging GDP to GTP on the alpha-subunit.
As soon at GTP binds, the beta-gamma subunit dissociates.
Then both the alpha-GTP and beta-gamma subunits can each interact with effector proteins.
To terminate, GTPass Hydrolyses GTP back to GDP, causing the alpha-GDP and beta-gamma subunits to reform an inactive complex.

99
Q

How do GPCRs ensure a specific response?

A

Activated GPCRs interact with specific types of G-proteins. Also the subunits only interact with specific effectors. Ensuring a specific cellular response.

100
Q

How does anenylyl cyclase work as an effector?

A

G-protein causes release of GTP-alphaS subunit, which increasing activity of adenylyl cyclase enzyme.
Causes conversion of ATP to cyclic AMP 2nd messenger, which can then interact with other targets, e.g. PKA.
Cyclic AMP-dependent protein kinase phosphorylates target proteins.

101
Q

How does Phospholipase C work as an effector?

A

GPCR activated, forming alphaQ-GTP.
This then interacts with PLC, which cleaves PIP2 to generate IP3 and DAG.
IP3 interacts at ER stores, mobilising Ca2+.
DAG activates its own protein kinase C, which can phosphorylate molecules.

102
Q

Describe signal amplification

A

Relatively modest changes in conc. of molecules outside a cell, can cause quite large effects inside the cell.
E.g. Adenylyl cyclase activation generates many cyclic AMP molecules which then activate other enzymes.

103
Q

How is the force of contraction of the heart increased?

A

Adrenaline interacts with beta1-adrenoceptors in the heart.
This converts alphaS-GDP to alphaS-GTP, which then interacts with adenylyl cyclase to generate cyclic AMP. This activates PKA, which phosphorylates ventricular targets (VOCCs), allowing Ca2+ influx. Aswell as inducing CICR from Intracellular stores.

104
Q

How do you calculate molarity?

A

Molarity (M) = Grams/L / Molecular weight.

105
Q

Which property ensures an agonist binds to a receptor?

A

Affinity

106
Q

What property ensures activation of an agonist-ligand complex?

A

Intrinsic efficacy

107
Q

Which property ensures an activated agonist-ligand complex induces a response?

A

Efficacy

108
Q

What is Kd?

A

The dissociation constant. It is a measure of affinity. It is the conc. needed for 50% occupancy of receptors. Hence lower Kd = higher affinity.

109
Q

What is EC50 in terms of drugs?

A

The effective concentration giving 50% of max. response. It is a measure of potency. It depends on both affinity and efficacy, aswell as the number of receptors.

(Emax is the maximum response)

110
Q

What is the significance of spare receptors?

A

Some tissues have more receptors than required to produce the maximum response. They increase the sensitivity, allowing responses at low agonist concentrations.

111
Q

Explain partial agonists.

A

Partial agonists cannot produce the max. response, even with full receptor occupancy. the EC50 is equal to Kd.

112
Q

What indicates intrinsic activity?

A

Maximal response. Partial agonists have lower efficacy than full agonists.

113
Q

Explain reversible competitive antagonism.

A

Increase [antagonist] leads to greater inhibition.

Can be overcome by high [agonist].

114
Q

Explain irreversible competitive antagonism.

A

Occurs when antagonist dissociates slowly or not at all.
With increased conc./time, more receptors become blocked. This is non-surmountable. Can suppress max. response at higher concentrations as insufficient receptors as they are blocked.

115
Q

Explain non-competitive antagonism

A

Allosteric binding of an antagonist to a receptor (not at the ligand binding site). Hence no competition for binding site.
Binding at this other site can alter the affinity/efficacy of the actual agonist. Could even inhibit the ability of the agonist to evoke a response.

116
Q

What is the oral bioavailability of a drug?

A

The proportion of drug given orally, that reaches the systemic circulation in an unchanged form. It is affected by first pass metabolism and gut absorption.

117
Q

What is the therapeutic ratio?

A

=maximum tolerated dose/minimum effective dose

=lethal dose to 50% people (LD50)/effective dose to 50% people (ED50)

118
Q

Describe first pass metabolism

A

Substances absorbed from ilium’s lumen enters venous blood, which drains into hepatic portal vein and taken directly to liver.
This drug may then be extensively metabolised in the liver. The parenteral/sublingual/rectal routes can avoid it)

119
Q

What is the role of class 1 (object drug) and class 2 (precipitant drug)?

A 
The class 2 drug is used at a dose greater than the number of binding sites and thus displaces the class 1 drug. This raises the free levels of the object drug and therefore higher risk of toxicity. 
Although free drug levels rise, elimination rate also rises.
120
Q

What is 1st order kinetics?

A

When the rate of elimination is proportional to drug concentration. A constant fraction of drug is eliminated in unit time. This gives a straight line when a log scale is on the y-axis versus time.
This gives a predictable therapeutic response from dose increases.

121
Q

What is zero order kinetics,

A

The enzyme is saturated. The rate of decline of plasma drug level is constant, regardless of concentration. This gives a straight line when normal plasma concentration is plotted against time.
This gives a therapeutic response that can suddenly escalate as elimination mechanisms saturate.

122
Q

Describe phase 1 liver metabolism.

A

A reactive group is exposed on the parent molecule, generating a reactive intermediate that can then be conjugated.
Mainly done but oxidation, reduction and hydrolysis.
Requires cytochrome P450 system, and a high energy cofactor NADPH.
Some drugs already have a reactive group so can bypass phase 1.

123
Q

Describe phase 2 of drug metabolism.

A

The reactive intermediate is conjugated with a polar molecule to form a water soluble complex.
Most commonly with glucoronic acid, sulphate ions and glutathione.
It requires specific enzymes and a high energy cofactor UDPGA.

124
Q

How are drugs excreted via the kidneys?

A

Only unbound drug is filtered here. Drugs can be actively secreted by the tubules.
Urine pH determines how much of the drug is excreted as passive reabsorption of drug is dependent on pH.
For weak acids, making the urine alkaline will make the drug ionised, so there will be less tubular absorption, because the charged drugs stall in the tubule lumen.

ESA 2 (7 decks)

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