MAR Flashcards
(152 cards)
1
Q
What are the functions of biological membranes
A
- Isolate ionic gradients
- create a closed of chemical environment
- selective permeability
- communication by expressing ligands and receptors
- facilitate electrical transduction
2
Q
Describe the approximate composition of membranes in terms of fat, protein and carbs.
A
40% lipid, 60% protein, 10% fat (doesnt add up but was what norman said)
3
Q
What is the role of cholestrol in the plasma membrane
A
Hydrogen bonds to fats and rigid tail reduce movement of phospholipids and decrease fluidity.
4
Q
what are the methods of movement of phospholipids
A
fast axial rotation, flip flop, flexion/intrachain motion, lateral diffusion.
5
Q
what is the composition of a pure bilayer
A
phospholipids, or glycolipids (cerebrosides and gangliosides)
6
Q
what are the characteristics of lipids in the bilayer?
A
16-18 carbons long, and can be unsaturated giving rise to a kink that can increase phospholipid spacing.
7
Q
what is the evidence for proteins in the plasma membrane?
A
observational- Freeze fracture of crystals and then using osmium to create shadows in electron microscopy, also centrifuge and lysis of RBC and then SDS page.
indirect- Observation of concentration gradient and active transport and also specific cell responses.
8
Q
What is the evidence for lateral diffusion of proteins and phospholipds?
A
Marked with specific antigens/tags and then observe how the patterns of the antigens/tags change around the bilayer.
9
Q
what methods of movement are avaiiable to proteins?
A
rotation, lateral diffusion, conformational change. NOT FLIP FLOP
10
Q
How are proteins kept in specific locations in the cell membranes?
A
some prefer cholestrol rich (signalling proteins), intracellular adhesion, extracellular tethering, aggregation.
11
Q
What does a hydropathy plot reveal?
A
it shows the regions of a protein that are either hydrophobic or phydrophillic. Can be used to show the number of times that a protein crosses a membrane.
12
Q
How can proteins be removed from the phopholipid bilayer?
A
the hydrophobic regions can be removed by biological detergents and the hydrophillic regions can be removed by altering the ionic bond strength by changing ionic changes and pH.
13
Q
describe the role of spectrim and relate this to its structure. How does actin relate to this role?
A
Spectrim is a heterodimer that forms the cytoskeleton in each cell that attaches to proteins in the plasma membrane. Actin forms cross links enabling the spectrim to attach to the plasma membrane.
14
Q
Describe two genetic diseases of spectrin
A
Spherocytosis- 50% deficiency in spectin levels
Eliptocytosis- defect in produced spectrin.
15
Q
Describe how multiple membrane domains are produced in the ER
A
The first membrane spanning domain is produced through a 20 amino acid region being produced after the initial signal peptide. This region is hydrophobic and so remains in the membrane forcing the ribosome to detach. The next domains are created in pairs that are then brought intogether in tandem.
16
Q
Describe how orientation of peptides is estabilshed
A
If the signal peptidase is cleaved during the process of translation then the C terminal will be external, if cleaved afterwards then the C terminal will be internal to the membrane
17
Q
What can and what can’t pass through a phospholipid membrane?
A
Can- small uncharged particles (oxygen nitrogen, benzene and carbon dioxide.) and small polar molecules (water urea and glycerol)
Can’t: large polar molecules (sugars and amino acids) and charged particles (any ions).
18
Q
Why are their processes to transport species across the cell membrane?
A
Metabolites in and waste out, Ionic gradients need to be estabilished and linked to this is both cell volume regulation and also electrical conduction.
19
Q
What equation dictates the rate of transport of a substance across a cell membrane?
A
Rate=Pc(C1-C2)
Pc=permeability constant
C1=Outside concentration
C2=inside concentration
20
Q
What is the difference between a pump and an exchanger?
A
Pumps= activity is coupled directly to the hydrolysis of ATP to ADP and use this energy directly to move the ions whereas Exchangers use already existing ionic concentration to facilate the movement of other ions.
21
Q
What are the intracellular and Extracellular concentraions of K+, Na+,Ca2+, Cl-, and A-?
A
Intracellular: K+(155mm), A-(167mm), Na+(12mm), Ca2+(10^-4mm), Cl-(4mm)
Extracellular: A-(40mm), Na+(145mm),K+(5mm),Ca2+(1.5mm), Cl-(123mm)
22
Q
Assuming permeability is not an issue, what dictates what direction ions will flow when placed on one side of a membrane?
A
The chemical gradient combined with the electrical gradient. Ions will want to increase entropy and so move to an area of lower concentration. They will also want to move to the area of most electrical attraction/least electrical repulsion. So a +ve ion will want to move to a negative location. This is united in the nernst equation that gives the Equilibrium potential for any ion (the goldmann equation gives the combined Eqs of multiple ions.
23
Q
How can ion channels be activated?
A
They can be gated for ligands, physical pressure and voltages
24
Q
What are the properties of ion channels?
A
Proteins, gated, selectively permeable, allow facilitated diffusion, saturatable (so have a Km and a Vmax).
25
Name the ion channels involved in Ca2+ influx/efflux, their location, stimuli and properties.
Mitochondrial cell uniporters- through facilitated diffusion and is due to -ve charge of matrix.
PMCA- Uses ATP to pump Ca2+ out, high affinity low capacity, upregulated by calmodulin, a protein in the cell that can bind Ca2+.
NCX- Usually move Na+ in and Ca2+ out but when high Na+ in or when cell membrane is depolarised it can operate in reverse.
SERCA- On S/ER and pump Ca2+ into the SER using ATP.
IP3r-Bind IP3 released from PIP2.
AMPA/NMDA- bind glutamate allowing calcium influx.
VOCC- present at synapses and in transverse tubules to allow the depolarising of the membrane to activate them. Upregulated by phosphorylation from PKA and inhibited by beta-gamma subunit from μ-opiod receptor.
Ryanodine- activated by cystolic CA2+, also by ryanodine which is a plant alkaloid.
26
What is the role of the NA/K atpase?
3Na+out/2K+ in.
Contributes 10mv to the overal -ve P.D
Largest role is to create the Na and K ion gradients between inside and outside, this then allows them to diffuse down their gradients which like in the case of muscle contraction or nervous elctrical conduction requires changes in the P.d of the cell.
27
What exchangers are needed to regulate cell pH?
AE- Acidifies cell by removing (HCO3-) for a Cl-
NaBC- Alkali influx due to Na and HCO3- being contransported.
NHX- De-acidifies cell. Loss of H+ ions.
28
How is cell volume regulated? What are the mechanisms of this?
By controlling the levels of osmolytes within the cell. H2O is attracted to charged particles with high charge densities. These mechanisms must be electroneutral otherwise cell PD is affected. examples could be both K+ and Cl- influx/eflux, or H20 and CO2 being turned into H+ and HCO3- and vice versa.
29
Why is calcium conc so low in the cell and relatively high externally? What are the advantages/disadvatages of such a system?
CA2+ is toxic at high doses as reacts with phosphate to form an insoluble precipitate. It also activates many cellular processes in an uncontrolled manner so can cause cell death/apoptosis. The tight regulation allows Ca2+ to be used as a signalling molecule as a small change can have a huge effect due to the cell being sensitive to change. However this gradient is very energy exspensive to create.
30
What is the role of NCX in ischaimia?
No 02=No ATP, NO ATP=high inward NA+ gradient, so NCX could flow in reverse allowing Ca2+ in resulting in cell injury.
31
Describe bicarbonate reabsorption in the proximal tubule of the kidney.
NHX pulls NA in to cell and H into lumen. H reacts with HCO3 forming H2O and CO2. These can then diffuse into the cell. Carbonic anhydride acts again reforming H2CO3. H then goes out of NCX. HCO3 goes out of AE.
32
Describe the action of Loop diuretics
Block NKCC2 in thick ascending limb. Dont affect ROMK, NAKatpase, or KCLct.
More effective treatment for people with renal deficiency.
33
How does amiloride function?
Blocks ENaC in the distal convoluted tubule.
34
what are the resting potentials for smooth muscle cells, neurons, cardiac myocytes and skeletal muscle?
-50mV, -70mV, -80mV, -90mV.
35
How is the resting potential set up?
Na/K atpase increase K+ conc inside and Na+ outside. K+ channels are open allowig it to diffuse down its concentration gradient (leak channels) towards its equilibrium potential. The -ve membrane potential arises as the large -ve proteins in the cell cannot follow K+ outside the cell and so remain. This results in the membrane becoming polarised. There is a degree of "leak" from Na and Ca ion channels which prevent the cell membrane reaching the Ek.
36
In what ways can a membrane potential change? describe some of the mechanisms.
By changing permeability to particular ions depending on whether one wants to depolarise or hyperpolarise the cell membrane. This can be facilitated into both excitory and inhibitory mechanisms.
This can be subdivided into fast and slow action.
Fast actions are EPSP and IPSP. EPSP are caused by binding of Ach and glutamate allowing influx of Ca2+ or Na+. Glutamate binds to AMPA and NMDA in the CNS. EPSP are triggered by influx of Cl- or K+ efflux. The role of EPSPs is to increase the excitability of a cell and an IPSP decreases this excitability. The slow signal transduction pathways are through G-Proteins. These can either modulate ion channels directly are change cellular process and affect them indirectly.
37
How is it possible to investigate action potentials?
Voltage clamping- Fix the voltage of the membrane and observe current flow.
Patch clamping-looking at the effect on one particular ion channel.
Current clamping- Fix the current and look at how p.d is affected.
38
What is the equilibrium potential for Ca, Na, K and CL respectively?
```
dependent on ionic concs
but Ca: 130
Na: 66
K: -90
cl: -96
```
39
Describe the influx/efflux of ions that contribute to the action potential.
Slow depolarisation until threshold. Then large influx of Na+. Na+ influx stops and K+ efflux begins causing a depolarisation. Hyperpolarisation occurs and then the resting membrane is restored.
40
What is accomodation and how does it affect the action potential?
This is the slow inactivation of VONaC. This due to "noise" that is present that causes the cell to become desensitized to this stimulus so requires a larger stimulus to get a full blown action potential. Inactivation occurs when an individual channel is turned on the inactivation particle gets lodged in the pore stopping ion passing through.
41
Describe the structure of a VONaC.
4 subunits that come together that are one continuous polypeptide. In each subunit there is a +ve charged 4th unit of out 6.
42
Describe the structure of a Potassium channel
Similar to VONaC only each subunit is a separate polypeptides. These come together to form the pore.
43
What is the maximum conduction rate and relationship of V and diameter of an unmyelinated neurone? a myelinated neurone?
- 20m/s and V is proportional to root d.
| - 120m/s and V is proportional to d.
44
What factors affect rate of electrical transmission?
Diameter of axon
| Presence of myelin.
45
Why does myelin increase rate of conduction?
λ= root(Rm*r/2Ri) c=(Q/V) V=Ed
Myelin increase Rm and also d thefore λ will increase (x100) and also Vmax will increase. So the capacitance of the descrease (x100)
myelin also has small gaps called the nodes of ranvier which allows for saltatory conduction and due to the increased length constant this is possible.
46
what can decrease the amount of Rm?
more ion channels open in the membrane
47
Describe a competitive and a depolarising channel blocker.
- Tubocuraraine: binds competively to a NAchR in the place of Ach and so stops channel activation.
- Succuinylcholine: Mimics Ach and binds to receptor but it cant get broken down. It leads to an initial influx and then a sustained inactivation of the membrane ion channels.
48
Describe mysathenia gravis
Caused by antibodies binding to NAchR which result in their demise. So a quantum of Ach has a smaller effect and so a larger release is required to have a normal effect. This manifests as muscular weakness and easy fatigability. Also it can be observered that it results in smaller MEPPs.
49
What is a MEPP? hypotheticall how could myathenia gravis, botulism, hypocalcimia, and pesticide poisoning affect them?
Mini end plate potential. Triggered by the release of one vesicle of Ach. smaller, less frequent, no change, elongated?
50
What is the sequale of action at the NMJ?
Action potential reaches the synapse
VOCC open allowing an influx of Ca2+ into the cell
This binds to synaptotagmin.
This protein then moves the vesicles down to the cell membrane.
Vesicle binds to snare complex which opens a pore. This allows the diffusion of the Ach into the synaptic cleft. Ach then diffuses across the cleft to open Nachr. Ach-esterase breaks down the Ach to choline and acetate.
51
Describe the NAchr
5 subunits. 2 alpha sub units bind the Ach and undergo a conformational change.
Pore is not very selective and allows Na and K to diffuse across.
52
What medication can be used to block VOCC?
L-type: DHP and are found in muscle neurones and in the heart.
N-type: omega connotoxins found in the CNS
53
How is the SER refilled with Ca after it has been depleted?
in muscle the majority of ca efflux is then sequestered again. In other cells, STIM is a protein embedded in the membrane that undergoes a conformational change when it doesn't bind Ca. This can then act on ORAI which causes an influx of Ca into the cell.
54
How does the cell buffer calcium levels to stop levels rising to high systemically thorough the cell?
through the use of calcium binding proteins i.e calbinding and calsequestrian. However if these are saturated then buffers will have a reduced effect.
55
How is the IP3 receptor activated?
GPCR activated on the surface that is coupled to a G protein containing alpha-Q. This activates phopholipase C that cleaves PIP2 into IP3 and DAG. IP3 then binds to the IP3r on the S/ER and causes a release of Ca2+.
56
What is the role of mitochondria in the regulation of cellular calcium?
Has a calcium uniporter that takes up calcium from the cystol at high concentrations. These are placed strategically in the cell so mitochondria are found in places where the cystolic concentrations may locally be very high.
57
What are the different methods of using proteins to effect the intracellular physiology due to a ligand?
Proteins with intergral ezymatic activity
Ions channels
Coupled effector and Receptor (GPCRs
Nuclear DNA receptors.
58
Why does evolution favour GPCRs?
Due to a defect in one doesn't affect the function of the other. So function is less likely to be lost entirely. This cannot occur in ion channels or proteins with intrinsic enzymatic activity.
59
What is the difference between a receptor and an acceptor?
Receptors are switched off until the ligand binds however acceptors undergo allosteric upregulation as they are active in the absence of the ligand.
60
What are the types of signalling molecule?
Hormone, paracrine, neurotransmitter, cell surface bound signalling ligands.
61
Name 3 tyrosine kinase plasma membrane proteins
EGFr, Insulin, PDGFr
62
Describe how a tyrosine kinase protein functions and how it would affect the cell physiology.
Always a dimer. Outer protein undergoes change upon binding ligand. This causes tyrosine kinase to autophosphorylate the inner section of the protein. Either an enzyme of a domain transducer will then bind with an SRC homology domain 2 which will then be phosporylated activating it.
63
What is a ligand?
A species that can bind to the receptor and can be an agonist or an antagonist.
64
What is a receptor?
A protein that can recognise a ligand and as a result of binding the ligand will regulate a cellular process. It is inactive completely when it is not bound to the ligand. Receptors have very low Kd so only require low concentration of ligand to effect a response.
65
How are receptors classified?
Classified based on what is bound and then sub classes can be built on the affinity of the ligand binding,
66
How do intracellular receptors function?
Protein has a DNA binding (zinc fingers) site that is covered by an inhibitor. The ligand binds to another part of the protein and the inhibitor detaches allowing the protein to bind to the DNA.
67
what is the optimum ratio of axon diameter: axon + myelin diameter?
0.7
68
What are some examples of none classical ligand binding ion channel structures?
Ryanodine (4TMD), ATP K+ channel in pancreas, purinoreceptor (ATP binding NA/CA channel)
69
What is the classical ligand binding ion channel structure? making reference to any particular structures on the NAchR.
5 subunits- each subunit is composed of 4 TMD with the 2 forming the "pore". In NAchR Ach binds to the 2 alpha subunits opening the pore. The pore retains ionic specificity by having 2 rings of acidic residues above and below the pore that stop the passage of anions.
70
List some Ligand bindind ion channels, their function and their ligands.
IP3r- binds IP3 and causes a release of Ca
NAchR-binds Ach, allows cation movement
GabaR-binds gaba and allows Cl- influx
NMDA,AMPA-bind glutamate allow Ca influx.
71
Define endocytosis, how does this differ to phagocytosis?
Internalisation of particles outside of the cell. Phagocytosis has a zippering mechanism whereas endocytosis uses clatherin coatings to internalise vesicles.
72
What is the role of clatherin in the cell? what are the names of the similar proteins found in the golgi and ER respectively?
```
Form triskelions (3 light and 3 heavy chains) that aggragate on the cell surface membrane and pinch off into spheres. These spheres are self contructing and spontaneous. The shape of the structure is a mixture of hexagons and pentagons.
Cop II and Cop I respectively
```
73
How do cholera and diptheria toxin gain entry into the cell?
Bind to GM1 gangliosides in the pits and are internalised.
74
How do viruses gain entry into cells?
Binds in the clatherin pit and then once in the cell releases Genome. The trigger for this is the low pH in the endosome.
75
How does type 2 diabetes arise?
Insulin acts on cells due to high levels of sugar in the blood. If this is constantly high then there is a down regulation of insulin receptors and this is the first step. This then requires an increase in insulin secretion to illicit the same level of response as normal. Beta cells eventually die due to having to work too hard to maintain the new required insulin output. When both insulin deficiency and resistance are present then it is type 2 diabetes.
76
How do cells uptake cholesterol?
Cholesterol is insoluble in the blood and so is carried in LDL which are coated in phopholipid monolayers and also Apoprotein. the Apoprotein binds to a specific receptor in the clatherin pit and is internalised due to the self assembly of the clatherin coat. The clatherin coat is then removed using ATP and the vesicle fuses with the endosome. The pH is low and this causes the receptor and ligand to uncouple (CURL). The receptors are recycled and are taken back to the cell membrane (possibly via the golgi) and the LDL is degraded by the lysosome.
77
How do cells get transferin in and out of a cell?
transferin has a low receptor at physiological pH except when it is bound to FE3+. It gets internalised like in other cases and the clatherin coat is removed. At a low pH the transferin has a higher affinity for the receptor even when unbound to FE3+. So the ligand remains attached to the receptor so neither are degraded.
78
Describe the process of insulin receptor degradation
Both internalised and both end up in the lysosome. example of LDRD
79
When are both the receptor and ligand transported?
IGg- maternal to fetal circulation
| IGa- blood to bile
80
What proportion of drugs are currently aimed at GPCRs?
40%
81
What drugs are ligands for μ-opioid receptors?
morpheine, heroine, buprenorpheine
82
Give an example of a neuroleptic
Haliparidol
83
How does the diversity in G- proteins arise?
20 genes coding for alpha units
5 genes coding for beta units
12+ genes coding for gamma units
combined this gives over 1000 different combinations. However in the body the alpha unit has the greatest impact on the observed action of the GPCR. The main types of alpha sub unit are S, I and Q. there is also an alpha t1 in rhodopsin.
84
What is the action of G-alpha t1?
activates cyclic GMP phosphodiesterase.
85
Why is there such a variety of G proteins?
Due to the huge number of different stimuli that the body needs to be able to respond to (i.e light sounds smell taste hormones and large glycopeptides).
86
Describe the structure of GPCR.
has 7 transmembrane domains with an external n and c end inside. the c end communicates with the g protein. Ligands bind either deep between the domains or out on the the n terminus. typically large ligands bind to the n terminus and small ligands bind within the domains although this is not always the case.
87
Describe the change and resultant sequalae that arise as a result of the GPCR binding.
Conformational change in GPCR and G protein undergoes GDP for GTP exchange. This is a transient stage. The affinity for the alpha sub unit for the beta-gamma sumunit decreases so that they separate (the beta gamma subunit remains together). Both the beta-gamma sub unit and alpha unit remain in the plane of the membrane due to hydrophobic lipid soluble elements which enables the signal to be maintained in cell. The alpha subunit has a GTPase that has an intrinsic timer however this enzyme can be upregulated and downregulated by various proteins in the cystol.
88
What is the action of the cholera toxin?
cholera inhibits G alpha S GTP-ase and so results in the uncontrolled action of CTFR pump.
89
What is the action of the whooping cough toxin?
toxin inhibits alpha-i GDP for GTP exchange and so no inhibition occurs.
90
How does morphine inhibit synaptic release of neurotransmitter?
Morphine binds to μ-opioid receptors. G- alpha i subunit activated, the beta gamma subunit inhibits pq vocc and so no Ach is released
91
Describe the various common alpha subunits, what receptors they are coupled with and the mechanisms and cascades they are involved in.
i, α2 M2 D2 μ-opioid , inhibit adenylate cyclase, so lower cAMP so less PKA activated
s, B1 B2 D1 H2, activate adenylate cyclase so higher cAMP, so more PKA activated
q, α1 M1 M3 H1, more phospholipase C, so more PIP2-->IP3 + DAG, so IP3 receptor activated so calcium efflux, also there is an upregulation of PKC.
t1, transducin, upregulation of cGMP phosphodiesterase.
92
How does PKA function and how is it activated?
PKA is a 4 part complex. 2 regulatory and 2 catalytic. When bound together the enzyme is inactive. When cAMP binds to the regulatory section the catalytic sections are free to phosphorylate around the cell.
93
What effect does PKA have on L-VOCC?
it will phosphorylate it. The effect of this is to increase the Ca influx and so create a bigger trigger for contraction like in the heart and the action of adrenaline will result in an increase in inotropy.
94
Where in the body are alpha 1 receptors found?
GI tract/sphincters, veins, errector pilli muscles, seminal tract, radial muscle liver
95
Where in the body are alpha 2 receptors found?
pancreas, saliviry gland adipose, GI tract
96
Where in the body are beta 1 receptors found?
SAN, atria, ventricles, ANV, adipose
97
Where in the body are beta 2 receptors found?
bronchi, uterus, arteries to liver skeletal muscle and the small coronary arteries. also found in heart but less extensivley as beta 1.
98
Where in the body are M1 receptors found?
stomach, EPSP in autonomic ganglia
99
Where in the body are M2 receptors found?
SAN, AVN, parasympathetic nerve terminals.
100
Where in the body are M3 receptors found?
glands, bladder sphincter, Bronchi
101
What is Kd?
The concentration of ligand needed to get 50% binding of a receptor. This is a measure of affinity. The lower this value the greater the affinity.
102
What is the affect of having "spare" receptors?
Increased sensitivity to a ligand so ligand can be at low concentrations and still illicit a strong response. i.e 10% binding of M3=100% response. The response curve is moved to the left of the binding curve.
103
What contributes to potency? how is it calculated? what does this mean when % response/conc is shown graphically?
intrinsic efficacy,Affinity,Specific cellular constiuents
EC50= conc at 50% response
it means that a drug can have a higher potency then another by reaching the 50% level first despite having a lower maximum response.
104
How is Noradrenaline cleared and broken down in the body?
reuptake into presynaptic neurone and action of Catechol-O-methyltransferase and Monoamine oxidase.
105
What can be measured in the blood/urine as an indicator of the level of sympathetic activity?
plasma NA and A, O methylated derivatives
| Normetanephrine and VMA
106
How is NA packaged for release?
Packaged as dopamine and synthesised into NA before release.
107
What determines if a nerve terminal is dopaminergic or noradrenergic?
The enzymes that the neuron is expressing.
108
where is adrenaline secreted from?
Chromaffin cells in adrenal medulla.
109
Describe the metabolic pathway of adrenaline production including what key enzymes are involved
```
Tyrosine (tyrosine hydroxylase)
LDOPA (DOPA decarboxylase)
Dopamine (Dopamine beta hydroxylase)
NA (N methyl transferase)
Adrenaline
```
110
What is the advantage of synthesing a drug that interacts with only one receptor suptype?
Specificity of response in the tissue.
111
What enzyme is inhibited by alpha methyl tyrosine? when is this used in treatment?
Tyrosine hydroxylase, pheochromacytoma.
112
What is guanethidine? why is it no longer prescribed?
Replaces NA in vesicles and so blocks NA action. No longer used due to adverse side effects.
113
How is Ach synthesised?
By certain neurones from choline and acetyl-CoA by choline acetyl transferase
114
When would cerimeline be used?
to treat sjogrens syndrome. which is an autoimmune destruction of exocrine glands. cerimeline is an M3 agonist.
115
what is atropine and what is its clinical use?
muscarinic non specific antagonist. Can be used to block any M receptor i.e treat glaucoma and bradycardia.
116
Describe the structure of the eye and how treatment for glaucoma works in relation to this
radial muscle: as it contracts pupil gets larger.
inner circular muscle: as it contracts pupil gets smaller
cillalry muscle: as it contracts cilary body gets smaller and accomodation occurs. This allows for intraoccular drainage in glaucoma in both narrow and wide.
Canal of Schlemm: This faciliates the removal of the intraoccular fluid. Blockage of this stops flow.
Trabecula mechwork: debris can clog this reducing flow out of eye.
117
What is a partial agonist?
Binds to a receptor but isn't as good at inducing the intrinsic activity of the receptor as a full agonist.
118
What is an antagonist? What is its affinity and intrinsic activity? Who is the effectiviness of an antagonist measured?
Binds to a receptor (has affinity) but causes no change (no intrinsic activity). It is measured by IC50. the concentration of antagonism needed to reduce the response by 50%.
119
What are the types of antagonism? what types are surmountable and why?
competitive- surmountable by increasing conc of agonist as both ligands are competing for the same receptor so by increasing agonist the probability of it binding is higher than that of the antagonist.
Non competitive- Binds at an allosteric site. Doesnt affect Kd but will decrease maximal response as will be able to act regardless on the concentration of the agonist.
Irreversible- The greater the conc and the longer its been acting the less receptors available. So although might be surmountable initially as time progresses more receptors become unusable.
120
What is difference between a dose and a concentration?
Dose is the amount given as the concentration of the drug at the site of action is unknown.
121
Describe functional antagonism in the case of asthma
beta 2 relax airways- M3 constrict
122
How can drugs be targeted to receptor subtypes (using the example of salbutamol and salmeterol)?
Why would you want to do this?
salbutamol is 20 times higher affinity for beta 2 than 1. however it is given through inhalation so the majority of drug arrives at beta 2 receptors.
Salmeterol has an affinity of several 1000 fold so much higher affinity for 2 than for 1.
Specificity of response. The only designed response is in the lungs in this case so a less specific ligand could target the heart as well.
123
What are the methods of drug administration?
Oral, sublingual, rectal, SC, IM, IV, inhalation and transdermal.
124
What is the first pass effect?
oral drug intake means that the drug has to pass through the liver before it can reach the circulation. This can lead to extensive metabolism reducing the amount of drug that gets to the tissues.
125
What is oral bioavailibility? and how is it worked out?
the degree of drug this is available from oral intake compared to IV injection. its done as a simple division x100.
126
What is volume of distribution? What can increase it?
total moles of drug/conc of drug in blood
this gives a value in litres and the lower this value the greater the proportion of the drug that is in the blood. Low Vd means bound to proteins.
127
What effect does protein binding have on drugs?
can bind up to 90% of the drug, and if given with another drug can be displaced resulting in drug being pushed out of therapeutic range.
128
What is the theraputic ratio? what does it mean for treatment?
(Td50/ED50), the larger this value the greater the therapeutic window for treatment. e.g penicillin. The use of these 2 values allows the correct dosing to be given to stop the concentration going up to TD50 but also keeping the treatment effective by above EC50.
129
What is needed to get a drug into a steady state?
5 half lives time, maintainance doses and a loading dose initially.
130
What are the possible relationships between elimination and concentration? and what are the clinical consequences of increased drug concentration?
zeroth order- rate of elimination is constant, so if drug concentration increases massively TD50 could be exceeded.
first order- rate is proportional to concentration.
131
What drugs are affected first when there is a decrease in rate of drug metabolism?
Drugs which are used at the lowest possible effective concentration, drugs with a small therapeutic window, drugs that are metabolized at a zeroth order rate.
132
How can renal disease affect drug levels?
Increases half lives so longer needed to reach steady state, and protein binding may also be affected
133
How are drugs excreted in the kidney?
pH dependent passive re-absorption of lipid soluable non ionised drugs.
Acidic Urine= more HA then A- H+ so more HA absorbed.
Basic urine= more A formed then AH+ so more drug reabsorbed.
Ionised lipid insoluable drug passes out in the urine.
134
What would increase the rate of asprin clearence in the kidney
As Asprin acidic, basic urine= less HA so more clearance.
135
What is the role of the ANS?
To control all the invulunary functions within the body. Purely efferent but with afferent inputs.
136
Where in the CNS and Spinal cord in general do ANS fibres originate from?
lateral horn.
137
Name the key NANC transmitters
atp, NO, serotonin and neuropeptides
138
Where are M3 receptors find?
lungs, glands, penile erection, bladder contraction and relaxation (sphincter) and increased GI motility. Cilliary muscle and iris sphincter contraction.
139
Affects of NA on the body?
increased HR and heart inotropy, vasodilation in coronary vessels, vasoconstriction in vessels with alpha 1, bronchial/bladder and uterine relaxation radial muscle contraction. beta 3 receptors cause bladder sphincter contraction. Renin release.
140
Describe baroreflex failure?
Presents with hypertension (sustained of episodic)
| Due to damage to vagal or glossopharyngeal nerve, pheochromocytoma, or primary hypertension.
141
Describe Familial dysautonomia
Hereditary sensory and untonomic neuropathy.
Delayed speach, unsteady gait, spinal curvature, erratic and unstable blood pressure, poor growth, pain insensitivity, no tear production.
142
What are the common steps in neurotransmitter production and release that tend to be targeted by drugs?
degradation of transmitter whilst in the cytoplasm
blocking of the post synaptic receptor
inactivation of neurotransmitter
re-uptake of transmitter
interactions with the presynaptic receptors.
143
How is acetylcholine produced?
AcetyleCoA + choline--> acetyle choline and CoA
| Done by choline acetly transferase
144
How is Ach degraded?
Ach--> acetate and choline
| Done by acetylcholinesterase.
145
What is the problem with muscarinic acting drugs?
Act systemically due to the lack of specificity that has been achieved
146
How does pilocarpine treat glaucoma?
Acts to induce contraction of the cillary muscle and also the iris sphincter. This allows more aqueous humor to leave the eye via the canal of schlemm.
147
What are presynaptic varicosities?
Widenings in the nerve that are designed to store and production of neurotransmitter. Each one is a specilised centre for Ca2+ dependant NA release.
148
Describe the process of NA synthesis
tyrosine-->DOPA-->dopamine-->NA
| inhibited by alpha methyltyrosine
149
Describe how NA is stored
sequestered in vesicles as dopamine by VMAT
| inhibited by reserpine
150
How is NA released?
Vesicles bind to presynaptic membrane in response to Ca2+ influx.
ive feedback from an alpha 2 receptor in this process makes it a target for alpha 2 agonists. This is due to the inhibiting of VOCC by the beta gamma subunit of G-alpha-I.
151
Describe the control over the NA reuptake
by a Na+ symporter.
152
Describe how NA can be broken down
The NA is broken down by MAO in the cell in excess. MAO inhibitors block this process.
