WHOLE MODULE Flashcards
1
Q
What is the relationship between Kd and DR
A
Inverse
2
Q
What does an agonist have to be able to do in order to be classed as a full agonist
A
Induce the max repsonse of the tissue
3
Q
What can be said about the ion turnover of facilitated transport proteins
A
It is high
10^2 - 10^3 ions / s
4
Q
what is the name of the transporter which allows Na to enter TAL cells
A
NKCC2
5
Q
What type of cells are increase in rheu arth patients
A
Th1 cells
6
Q
Does Kd always equal EC50
A
No
7
Q
ADVANTAGE/DISADVANTAGE
H3 OR I(125)
Difficult to incorporate ligand fue to high mass
A
Disad I 125
8
Q
What is occupancy dependent on
A
Drug concentration
9
Q
What is meant by aspiring being a suicide inhibitor
A
Permanently binds to XOZ
10
Q
ADVANTAGE/DISADVANTAGE
H3 OR I(125)
Biological act of the ligand can be reduced
A
Disad I 125
11
Q
Act of macrophages as a result of autoimmune resp leads to synth of which two pro inf mediators
A
Interleukin-1 (IL-1) and tumor necrosis factor a (TNF-A)
12
Q
What occurs when calcineurin is activated
A
Activation leads to removal of phosphate groups and act of TF NFKB that promotes transcription of pro-inflam chem/cytokines
13
Q
NAPQI toxic intermediate A or P
A
Paracetamol
14
Q
What is meant by physiological antagonism
A
When two or more drugs interact with opposing actions - or act through different transduction machinery
15
Q
What is the difference between the nernst and goldman equations
A
Nernst used to calc eqbm pot wherease goldman used to calculate the membrane potential
16
Q
Define specificity
A
the attribute that a drug will preferentially bind to one type of receptor over another
17
Q
What can usually be said of the metabolism of a drug which is rapidly absorbed from the drug
A
Metabolism will be fast
18
Q
Describe how allosteric modifications aid in acid extrusion
A
Protons other than the one being transported bind to the NHE protein and cause a conformational change that results in an increased rate of transport at higher protein concentrations
19
Q
Give examples of medications given directly to the skin
A
Nicotine patches, chronic pain treatments such as fentinon
20
Q
Who developed the patch clamp technique
A
Nehr and Sakman
21
Q
ADVANTAGE/DISADVANTAGE
H3 OR I(125)
High specific activities can be obtained
A
Ad H3
22
Q
Would a drug with a higher Kd be more or less potent
A
Less
23
Q
How can we classify facilitated transport proteins
A
Uniporters, symporters and antiporters
24
Q
What is the benefit of biologicals in treatment of autoimmune disease and how can this cause problems
A
More longer lasting (longer half life) and fewer off site effects, but can dampen down the immune system so more susceptible to infection
25
How many TM domains of VGKC
6
26
How many transmembrane domains does a GPCR have
7
27
Where is AE1 predominantly found - what is its main role
Red blood cells
| Creates the Cl-/Hamberger shift
28
Explain how particle size influences a drugs effectiveness
Larger particle sizes as are found in non-branded medication will more often be metabolised so less of that drug will have an effect. Smaller particles are more liekly to enter the blood stream
29
What prevents an acid from being absorbed into cells once it is dissociated
Acid group will have a negative charge and the cell is also negatively charged so will be unable to cross the membrane
30
What is the Cl/HCO3 exchanger primarily involved with
Involved in acid loading
31
What is they symptom patter of expression in rheum arth
Symmetricle (both sides of body effected)
32
By what mechanism is Ca kept low
Ca/Na exchanger and the CaATPase
33
Give an example of a drug injected into the CSF and how is this benificial
Epidural - pain relife given during labour - means that the patient isnt required to be unconscious
34
What would you see in the conc-resp curve for an agonist as you increase the conc of antagonist present in the system
Parallel rightward shift in the curve due to a higher concentration being required to elicit the same percentage response
35
Give an example of physiological antagonism
NAdr raises arterial BP by acting on the heart and peripheral blood vesssles while histamine acts to reduce arterial BP by causing vasodilation
36
How are some inflammatory mediatiors involved in homeostasis
PG A2 is a vasodilator, PGD2 inhibtis platelet agg and PG F2 is a bronchoconstrictor
37
What approximation can be used when plotting B/F against specific binding
Free ligand, F is the same as the concentration of the added ligand
38
Doubling the concentration of protons in solution would equate to a pH change of
0.3
39
What does NHE rely on
Inward Na gradient
40
How are some inflammatory mediatiors involved in the perception of pain
Some PGs increase the sensitivity of nociceptors to painful stimuli
41
How many TM domains of a VGNC
24
42
What is the preferred method for drug administration and why
Oral as tablets
| Convenient
43
Why is COX2 a desireable target for NSAIDS
Inhibiting its activity will have less impact on homeostasis, something which accounts for the side effects in COX1 inhibitors
44
What type of transport protein has the highest turnover of ions
Channel proteins
45
T/F
When combined with the gradient created by the Na/K ATPase the gradient created by the Ca/Na exchanger is equal to the Na gradient
True
46
A or P - reduced risk of colon or rectal cancer
Aspirin
47
What are NSAIS prescribed for genrally
Musculoskeltal pain
48
What is the name of the molecule that is converted into inflammatory mediations
Where is this molecule found
Arachidonic acid is produced from phospholipids from the membrane of the cell by phospholipase A2
49
What is the contribution of the Na/K ATPase to the Vm in MV
3mV
50
ADVANTAGE/DISADVANTAGE
H3 OR I(125)
Spec labs and equiptment required
3H disad
51
What accounts for the differences between COX1 and CO2 isoforms
COX1 has a bulky isoleucine at a position the COX 2 has a smaller valine, so channel in COX2 is wider
52
If only the K+ chanells are open why isnt Vm ~ Ek
Influence of other ions
| K leak channels (let Na through also)
53
What is the other name given to co-transporters
Symporters
54
How can we manipulate compartment pH in overdose situations
To prevent absorption of drugs that are weak acids in patients that have overdosed NaHCO3 is administered to neutralise the pH
55
Current measured in patch clamp technique is relative to
The ref electrode
56
Example of a ligand gated ion channel
nAchR
57
What happens once a drug that is a weak acid is absorped into the blood
pH of the blood is roughly neutral so more of the drug will dissociate
58
EC [Cl]
150 mM
59
What consituent forces make up the electrochemical gradient
Potential difference and concentration
60
Define equillibium potential
The Vm where there is no net movement of ions across the membrane and thus no current is meaured
61
What do microsomal enzymes act on
The inactive, uncharged drug once it has crossed the plasma membrane
62
What are the active sites of COX enzymes
Peroxidase AS and cycloxygenase AS
63
T or F Rheumatoid arthritus only presents around ages 40-60
F - can present in young adults and children too
64
What is meant by effiacy
The ability of the drug receptor complex to form an active complex which can induce a response in the target cell
65
IC [Ca]
2 mM
66
T or F
Polar molecules can dissolve freely in lipids due to their ability to interact with charged groups on the molecules thus enabling them to penetrate cell membranes freely
False
| Non polar/uncharged molecules can freely penentrate cell membranes, polar molecules can not
67
Is an exchange protein synonomous with an antiporter
Yes - same thing
68
IC [Na]
15 mM
69
What is recovery in Ph in a buffered system due to
Acid loading and extrusions
70
Other than B2 ad agons what is the most common asthma treatment
Glucocorticoids
71
A or P only competivie inhib
Paracetamol
72
How do NSAIDS prevent conversion of arachiodonaic acid to infl mediators
Block the channel in the COX enzyme preventing arachidonic acid entering
73
Give an example of a non comp antagonist
Dihydropyridines bind to and block Ca channels rather than the receptor (which is activated by Nadr)
74
What is the role of the chemoreceptor trigger zone in the brain and how can this lead to some side effects of drugs
CTZ is the area at the base of the brain responsible for nausea and the vomitting reflex
Some receptors can bind to these receptors and thus inappropriatly cause the this response
75
Upon what principle does buffering rely on
Ability of amino acids to act as proton acceptors/recievers
76
What three factors lead to est of the resting potential
Selectively permeable membrane
Unequal distribution of ions
Unequal distribution of physical forces (diffusion and electrochemical gradient)
77
How many subunits to the Na/K ATPase
2 alpha and 2 beta
78
3 As of NSAID effect
Anti-inflammatory, antipyretic, analgesic
79
How do large molecules pass the cell memebrane
Endocytosis
80
Agonists will have what degree of efficacy
High
81
What molecules do NSAIDs prevent the synthesis of
Prostaglandins and thromboxanes
82
How many IC domains does a nuclear recepotr have, why?
None
| Found IC
83
Define Ec50
The drug concentration at which the response is 50% of the maximal response
84
What fluid compartment would contain the highest conc of PO4(2-)
ICF
85
What ould be the expected efficacy value for a full agonist
1
86
Explain how inverse agonists work
Some receptors can adopt an active conformation without the presence of an agonist - inverse agonists bind to these receptords and stabilise their structure reducing and constitutive activity
87
How many ions can a channel protein hold at one time
Many
88
What sort of pH stimulates NHE
Acidic
89
Describe what happens in the induction phase of the immune response
APCs associate with CD4+ and CD8+ cells and act. Act CD8+ become Tc cells and kill cell. Act CD4+ begin to produce IL-1 leading to act and prolif of the Th1 cells. B cells also activated, transform to plasma cells and begin creating antibodies
90
Non competitive antagonism?
Do not compete with the agonist but block some steps in the process between receptor and resposne
91
Rate of excretion is INDEPENDENT OF _____ AND IS DETERMINED BY _____
Concentration
| Metabolism
92
What is the broad group of inhibitors of the Na/K ATPase
Cardiac glycosides
Ouabain digoxin
93
How do small molecules and ions move into and out of the cell
Via facilitated diffusion through transport proteins
94
How would the results of a radioligand binding assay what could be done
Bound ligand / Free ligand AGAINST specific biding
B/F against specific binding
95
How do low and high concentrations of ryanodine influence one of these Ca channels
Low concnetrations activate
| High concentrations inhibit
96
Since NKCC2 relies on the inward gdt of Na what would occur if Nai was increased
Transepithelial osmotic gradient reduced/dissipated so Na and Cl reabsorption is inhibited
97
What is meant by receptor reserve
More receptors present than the tissue needs to cause a maximal response
98
ADVANTAGE/DISADVANTAGE
H3 OR I(125)
Long half life
Advantage of 3H
99
How does the Na/K ATPase contribute to the Vm
Directly and indirectly
100
What affects drug absoption
Method of admin, size/Mr, lipid solubility, carrier mediated transport, pH/ionisation state
101
What is the TAL reponsible for
reab of Na and CL
102
ADVANTAGE/DISADVANTAGE
H3 OR I(125)
Safer to use
Advanatage of I 125
103
Where is the ligand binding site found in ligand gated ion channels
On EC surface at the amino terminal
104
How is the issue of non specific binding overcome
Excess of cold ligand, added to second population of test tubes that will displace only selectively bound radioligands.
Comparision between the radiation readings of the displaced selectively bound ligands and the non displaced radioligand will give you the ammount of non selective binding
105
What other factor influences the rate of transport by the Na/K ATPase
[ATP]
106
How are some inflammatory mediators involved in the preception of pain
Some PGs increase the sensitivity of nociceptors to painful stimuli
107
In what circumstances may rectal administration be favoured
In children who cant swallow tablets
| In people who can swallow/vomitting
108
What effect do NSAIDs have on BP
Increase
109
ADVANTAGE/DISADVANTAGE
H3 OR I(125)
Very high specific activities for aromatic hydroxyl groups
I 125
Advanatge
110
What are the 7 methods of drug administration
```
Percutaneous
IV
Intramuscular
Intrathecal
Oral
Rectal
Inhalation
```
111
Name the NSAID with a higher selectivity for the COX2 isoorm
Diclofenac
112
What are the two main factors which influence drug distribution in the body
Binding to plasma proteins e.g. albumin
| Partition into specific tissues e.g. body fat, bones and teeth
113
Define efficacy
Ability of the drug receptor complex to induce further signalling
114
Define antagonists
Drug that prevents the aciton of an agonist
115
If the curve plotted from data collected during a radioligand binding assay doesnt reach a saturation point, what can be inferred
Some non-specific binding is occuing
116
What is another word for a primary active transport protein
Pump
117
EC [Ca]
2x10^-4 mM
| 20 nM
118
How can we measure pH in large cells
Two electodes, one to measure the potential of the entire cell, the othr measures the potential as a result of all ions except H+
This difference between the two values is proportional to the pH
119
How many TM domains does the NHE have
12
120
Which receptor family only has a single TM domain and all of its ligans are peptides
Kinase linked receptors
121
What are 4 classes of allergen
Inhaled mat, injected mat, ingested mat and contacted mat
122
What does NSAID stand for
Non sterioidal anti inflammatory drugs
123
VGCC are found on _______________ cells and are activated by ________
electrically excitable cells
| Depolarisation
124
What does NSAID statnd for
Non-sterioidal anti inflamatory drug
125
Give an example of a DMARd and how it works
Methotrexate - inhibits the activation of Th1 cells thus preventing inflammation
126
What are the main types of triggers of asthma
Atopic (allergies) non-atopic (cold)
127
What causes nausea and stomach pain as a reuslt of NSAID use
PGs inhiibit acid sec and protect gut mucosa - less production can lead to ulceration of GI tract
128
[Na]o
145 mM
129
What is the efficacy of an invrse agonist
Less than 0
130
ADVANTAGE/DISADVANTAGE
H3 OR I(125)
More readily degraded
Disad of I 125
131
By what mechanism do kinase-linked receptors work
Agonist binding activates the kinase carboxyl terminal or the acitvated receptors recruit and IC kinase
132
What is plotted graphically in a Schild analysis
Log (DR-1) against log [antag]
133
What factors does Ec50 depend on
Efficacy
Affinity
Number of receptors
134
Is COX2 constit active
No is only activated in infalmmatory conditions
135
[Ca]o
1 mM
136
How can glucocorticoids be used in the treament of rheu arth
Glucocorticoids inhibit the action of TFs that usually promote the transcriptio of pro-inf cytokines
137
T/F
| Proteins act to puffer changes in pH which can result in a change of conformation and/or loss of functions
T
138
[Ca]i
100 nM
139
What are the four main ways drugs are eliminated from the body
Exhalation, excretion in the urine, binding to food stuff being excreted in faeces, and presence in sweat and milk
140
EC [K]
5 mM
141
What can be said about the DR for an antagonist with a high Kd
High Kd means a smaller DR
142
What can be a problem of administering drugs directly to the lungs via inhalation
A large proportion of the drug is expired
143
Explain how the _______________ achieves acidifcation
Cl/HCO3 exchanger
Inward movement of CL- in exchange for HCO3-
Removal of bicarbonate leaves protons produced by the reaction of water and CO2
144
At rest what can be said about perm of the membrane to Na and K
Membrane more permeable to K than Na
145
Act of Th1 cells causes release of which family of inflammatory mediators
Cytokines
146
What TM domains of NHE are involved in Na transport
4 and 5
147
What is sig about intrathecal drug elimination
Intrathecal fat soluble drugs are metabolised poorly - they must conjugate on order to get trapped and be excreted in the urine
148
Composition of lipids in the membrane
42%
149
How does the ammout of inhibition change with a irreversible antagonist over time
Increases (inhibition) over time
150
Composition of proteins in the cell membrane
55%
151
What are the four areas to consider in pharmacokinetics
Drug absorption, distribution, metabolism and excretion
152
ADVANTAGE/DISADVANTAGE
H3 OR I(125)
Short half life
I125 disad
153
Is the resting membrane potential the same in all cells
The membrane potential is mainly negative but varies in magnitude
154
IS the exchange of Cl and HCO3- independent of Na
YES
155
What are the different types of Ca channels in store membrans
IP3 receptors and ryanodine receptors
156
What do occupancy and efficacy span from
0 - 1
157
Are more proteins found in the ECF than the ICF
Yes
158
A or P COX3 selective
Paracetamol
159
What does a high Kd indicate
Low affinity
160
Explain how action of aspirin leads to the duration of its effects
As aspirin binds permamnetly its duration lasts until all new enzymes have been synthesied usually aorund 4 hours
161
Where does the other 80% contribution of the Vm come from
K+ channels - movement of K out of the cell through K channels creating a negative charge inside of the cell and a potential difference between the two sides
162
Well absorbed and metabolised by the liver A or P
Paracetamol
163
Composition of carbohydrates in the membrane
3%
164
Vm
-70 mn
165
What is the function of ROMK in the TAL
K+ recycling across the membrane
166
What diuretic will have an inhibitory effect on NHE - what concnetration
Low concentration of amiloride
167
What is the name given to the class of small molecules used in rheu arth treatment
Disease modifying anti-rehumatic drugs
168
A or P - Weak acid, rapid and efficient absorption
Aspirin
169
What three properties determine the effect of a drug in a living system
Specificicty, affinity and efficacy
170
How many ions are removed from the cell and how many brought in the the Na/K ATPase
3 Na O
| 2 K I
171
What is the tunrover of active transporters
Low turnover
| Less than 100 ions per second
172
What is the name of the enzymes inhibited by NSAIDs `
Cyclooxygenase enzymes (COX)
173
Are facillitated transport proteins selective
Yes - highly
174
Other than the hamberger shift what is another role of AE1 in the red blood cell
Long c-terminus links to the cytoskeleton helping to stabilise the membrane
175
How is it possible for EC50 to be lower than the concentration req to occupy 50% of the total receptors (Kd)
IC signalling cascades can amplify
| Receptor reserve
176
Through which recepotrs do Abs involved in the IR bind and where are they locates
IgEs bind to IgE Fc recepotrs on the surface of mast cells found in the skin and mucous membrane
177
Can drugs be 100% specific
No drug absolutely specific, high enough concentrations of any drug will cause it to interact with other receptors
178
What does the Na/K ATPase regulate
Intracellular ion concentratiosn
179
Explain how the equiptment used in the measuring of pH using floourescence is calibrated
Membrane is permeabilised using a protein ionophore and the pH of the bath equated to IC pH
180
Explain how cyclosporine can be used to treat autoimmune diseases
Cyclosporine bines to cyclophillin and inhibits calcineurin which prevents the act of NFKB TF and reduces the transcription of pro infl cyto/chemokines
181
Explain how an increase in IC pH can be buffered
Dissociation of the carboxyl group on the amino acid is favoured releasing protons
182
What will happen to drugs a low pHs such as the one in the stomach, why is this benificial
Dissociation eqbm will shift to the left favouring the reverse reaction leaving more of the drug in its associated deom - this is benificial as more of the drug will be absorbed
183
What is equal at the equillibrium potential
Movement of ions due to potential gradient = movement of ions due to concnentration gradient
184
What type of drugs are the majority of clinical useful drugs
Antagonists
185
Define competive antaognism
Where an antagonist competes with an agonist for occupancy of a receptor
186
Describe the passage of lipid soluble molecules across the membrane
Simple diffusion
187
Give examples of lipid-soluble molecules that can cross the endothelial cells and enter the CNS easily
Ethanol and caffine
188
What is an issue regarding some of the drug being lost for the oral route of admin
Lose some of the drug to to metabolism in the liver/kidney
189
What is the chem name for aspirin
Acetylsalicylic acid
190
Which type of transport protein requires either an electrochemical gradeint of a concentration gradient
Carrier proteins
191
How are some inflammatory mediators involved in homeostatsis
PG A2 - vasodilator
PG D2 - platelet aggregation inhibitor
PG F2 is a bronchoconstrictor
192
When does the Cl/HCO3- become inhibited and when does its rate increase
Inhib at a low Ph
| Rate increases as it becomes more alkaline
193
What are tissue samples kept at low temps during radioligand binding assays
To minimise the activity of hydrolytc enzymes on the cells/receptors
194
When comparing multiple agonists on a conc-resp curve how can more potent agonists be distinguished
Conc-resp curve will be shifted to the left
195
What TM domains of NHE are involved in H+ transport
6 and 7
196
A or P Reduced risk of Alzheimers
Aspirin
197
ADVANTAGE/DISADVANTAGE
H3 OR I(125)
Labelling is expensive and difficult
Disadvantage 3H
198
Do active transporters work without or against a driving force
Yes
199
What type of molecuels is a radioligand binding asay useful for
Small molecules
200
Describe the pathogenesis of asthma
Trigger --> inf cells to airways -> release inf med such as histamine --> bronchoconstriction
201
What is the major concern with administering some drugs to patients of a high body fat
Drugs such as anaesthetics are highly lipid soluble and large ammounts of drug can be trapped in body fat
This means an increased dose of the anaesthetic is required in order to have the desired effect but also means the drug will remain in the body for longer
202
What determines how quickly biologicals injected into muscles enter the blood stream
How well perfused the muscle is
203
What is calcineurin
A phosphatase found inside T cells that is regulated by Ca
204
How does the reanl exretion of penicillin and diazepan differ
Penicillin cleareed in one pass
| Diazepan is extremely lipophilic and is thus cleared from the body slowly
205
Is facilitated transport an example of a process which reaches saturation
yes
206
How much of the Vm value comes from the action of the NA/K ATPase
20%
207
What does the activity of NKCC2 rely on
Inward gdt of Na
208
What is the Goldman equation
61/z log ((PnaO + PkO)/PNaI + PkI))
209
Why is the movement of NA into cells generally through pathways with physiological significance
The ammount of energy required to establish this gradient initially is extremely high
210
What can be said about the Ca gradient
1000 fold difference so gradient will favour Ca entry into the cell
211
Is comp antag irreversibel?
No reversed by washing
212
What is the most important determinant of the pharmacokinetic characteristics of a drug
Lipid solubility
213
Are NSAIDs effective at treating chronic inflmmation
No is only activated in infalmmatory conditions
214
What can the Vm vary between
-80 -- -30mV
215
What is converteed into PGs and thrombx, what is produced from, what enxyme
Arachidonic acid - produced from PLS at the membrane by PLA2
216
Define occupancy
Total number of receptors occupied at a specific drug concentration over the total number of receptors present
217
T or F People with a predisposition to an allergic phenotype are more likelt to develop allergies
Yes
218
What is significant about the B/F against specific binding graph
Gradient is -1/Kd
219
What are the four protein targets of drugs
Receptors, enzymes, transporters/carriers and ion channel
220
How do pharmacokinetic antagonists work
Reduce the ammount of other drugs or alter drug metabolism
221
What does a low Kd indicate
High affinity
222
What is meant by electrogenic transport
Net movement of charge - charge creating
223
What class of immunoglobins mediates the immune response
IgE
224
ADVANTAGE/DISADVANTAGE
H3 OR I(125)
Danerous to deal with
Disad - 3H
225
Define dose ratio
The factor by which agonist conc is required to be increased by in order to elicit the same magnitude of response in the presence of an antagonist
226
What is the strucutre of COX enzymes
Made up of two identical subunits wth two active sites
227
What is the name for drugs which only become active once they have been ,etabolised and what is the advantage of this
Pro drugs
Slow release of drug and slower induction of effects
e.g. in sedatives and seizure controlling drugs
228
Example of a co-transporter
Na/Glucose co transporter
229
What is the equation that allows calculation of the total current carried by a population of ion channels
I = N . Po . g . (Vm - Ei)
230
Movements between compartments usually involves penetration of lipid diffusion barriers T or F?
T
231
What way do Ca/Na exchangers work in
Can work in both directions
232
What can be said about the relative permeabilites of Na and K at rest
Membrane is around 50-75x more permeable to K+ than Na+
233
How does excessive paracetamol lead to liver damage
Metabolism of paracetamol leads to production of NAPQi - hepatotoxic intermediate that is usually quickly converted but can build up in overdose situations
234
What happens once a drug that is a weak acid gets to the kidneys
Basic pH of the Kidneys (~8) will mean that the equillibrium will shift to the right favouring dissociation of the drug. This will prevent it from being reabsorbed due to the negative charge of the undissociated drug preventing it from crossing the cell membrane and therefore causing its excretion in the urine
235
Value of Eca
120 mV
236
What can be used in the long term to treat asthma
Long actin B2 ags like almeterol delivered with corticosteroids. Glucocorticoid such as beclomastone or antichloinergics like tiotropium brmide that blocks effects of endogenous Ach
237
What is 'gated pore' used to describe
Channel proteins
238
Which method of drug administration is preferred for biologicals
Intramuscular
239
By what two ways could Ca/Na exchanger be electrogenic
Ca is a 2+ ion and Na a 1+ ion
| Also 3 Na in for every one Ca out
240
What does the Na/K ATPase maintain
A low extracellular K concentration
241
How can you create COX2 selective NSAIDS
NSAIDs with bulkier groups can only fit into and inhibit the COX2 enxyme due to its wider channel
242
If a partial agonist has the same Ec50 as a full agonist what would happen to its efficacy
Efficacy would be lower
243
What can be the negative effect of phase I metabolism of small drugs
Can lead to the production of a toxic intermediate e.g. in paracetamol --> NAPQI
244
What is meant by drugs that exhibit zero order kinetics
Rate of elimination is constant and does not depend on or vary with the drug intake or plasma concentration of the drug
245
[Na]i
15 mM
246
What molecules do NSAIDS prevent synthesis of
Protsaglandins and thromboxanes
247
What do antagonists have an efficacy of
0
248
Why is COX3 a benificial target for NSAIDs
COX3 isnt expressed in the GI tract so its inhibition wont lead to gut irritation and stomach pain
249
What is meant by the term biologicals
Peptides which have been engineered to bind with drug-binding proteins
250
What is the most common type of assay used to determine the occupancy/affinity of a drug for its receptor
Radioligand binding assay
251
Ena
+60 mv
252
Define affinity
The ability of a ligand to bind to the receptor
253
Give an example of another drug that is partititoned to a specific tissue
Tetracyclin - binds tightly to calcium and so ends up trapped in bone and teeth
254
Give examples of some of the microsomal (IC) enzymes found in the liver that have roles in drug metabolism
Cytochrome P450, alcohol dehydrogenase, monoamine oxidase
255
ADVANTAGE/DISADVANTAGE
H3 OR I(125)
Easy and cheap in most labs
Advantage of I 125
256
IC [Cl]
13 mM
257
Approx Ena
=61 mV
258
Give an example of a pharmacokinetic antagonist
Opiates can reduce absoption of other drugs by biding to gut opiate receptors and reducing gut motility
259
What methods used to separate the unbound radiologand
Filtration or centrifugtion
260
Explain how a decrease in IC ph can be buffered
Addition of protons to the amino group is favoured removing protons from the system
261
What gene family and superfamily do the Ca/Na exchangers belong to
SLC8 gene family
CaCA superfamily
262
What method of drug administration is useful for slow continuous drug administration
Percutaneous admin
263
What can be said about buffers with regard to their ability to influence pH
Buffers act to minimise the magnitude of a change - but can't reverse or prvent such change
264
Binding of the Ig to its recepotr occurs after an allergen is detected T or F
F - IgE naturaly bound to receptor
265
Drug dose intervals aim to achieve a constant level of the drug, how is this achieved
Balancing the rate of excretion with the rate of absoprtion to maintain effective levels
266
What is aspirin and other NSAIDs prescribed for
Musculoskeletal pain
267
How can antiobiotics act as pharmacokinetic antagonists
Some antibiotics increase the metabolism of drugs like warafarin reducing its effective concentration in the blood stream
268
How is affinity measured
Dissociation constant
KD = (K-1) / (K+1)
269
How many TMs of VG CFTR channel
12
270
How would you tell the dif bet a drug with a higher Kd when plotted on the same hroup
The drug with the highest Kd will have its curve right shifted
271
Why does paracetamol have less side effects than aspirin
COX3 not present in the gut thus its inhibition would lead to Gi irritation and stomach pain
272
How does aceylsalicyclic acid prevent PG synth
Forms a permanent covalent bond with COX preventing arachidonic acid reaching the cyclooxygenase AS
273
T/F
| A high efficacy or affinity of an agonist will shift its concentration-resp curve to the right
F - will shift curve left
274
Other than DMARD and calcineurin what other methods are there for treating autoimmune disease
Monoclonal ABS which bind to infl mediators such as TNF-A and prevent inflam
275
Which ezymes does asprin show selectively for
COX1
276
Example of a GPCR
mAchR
277
Explain what the issue is with non specific binding
SOme of the radiologand will bind to i.e the test tube and will accouunt for some of the radioactivity reading
278
What is the role Cl/HCO3 exchanger
Adds protons into the cell
279
What happens to Na/H exchange at high pH
When pH rises above a setpoint NHE becomes inactive
280
A or P A weak anti inflam
Paracetamol
281
What can happen to the tight junctions between the capillary endothelium in the brain during inflamation
Can become leaky
282
describe mechanism of action for the Na/K ATPase
Na IC binds to the channel
Hydrolysis of ATP leads to phosphorylation of the channel and conformational change in the protein
Exposes Na to the EC domain and releases
EC K binds to the channel
Dephosphorylation and conformational change reverting the pump to original confirmation
Exposes K to IC domain - release
283
How can flouresence indicators be used to measure pH in cells
Lipid soluble inactive indicator introduced into cells which is then cleaved by naturally occuring IC enzymes. Indicator is then exicted with light of a specific wavelength and the ammount of emitted light of a second wavelength is measured where the ammount of flourescence is proportional to pH
284
In which sex is rheumatoid arthritus more common, how many times
3x more common in female
285
When plotted on a semi log graph - conc having a log scale describe the shapes of curved produced in a radioligand binding assay
Specific binding shows a sigmoidal curve - reaching point of saturation
Non specific level until very high concentrations where it begins to increase exponentially
286
What structures prevent water soluble molecules from entering the CNS
Blood-brain barrier
287
What can be said about the permeability of the mebrane to an ion if the Vm is close to the nernst of that ion
Membrane will be permeable
THE CLOSER THE VM IS TO EITHER Ek OR Ena THE MORE PERMEABLE THAT MEMBRANE IS TO THAT ION
288
What happens in phase I of small drug metabolism
Modified by enzymes in the liver which carry out catabolic reations
289
What are the units of affinity
Molarity
290
Where is COX3 found, what is it and what is it a target of
In the CNS, COX1 splice variant, target of paracetamol
291
CaM and PK-C bind to the ____________________________ of NHE to modulate the set point
Long intracellular c terminus
292
ADVANTAGE/DISADVANTAGE
H3 OR I(125)
Indisting from native compound
Ad H3
293
What three facotrs are involved in controlling IC pH
Buffering
Acid extrusion
Acid loading
294
Rough [A-} IC valie
-65 mM
295
What are some long term side effects of long term glucocortiocid use
Muscle wastage, necrosis of femoral head, inc abd fat, buffalos hump, poor wound healing, tendency to hyperglycamemia, cataracts ect.
296
Come symptoms of rheumatoid arthritus
Joint pain, swelling, stiffness and poor sleep
297
The Na/K ATPase is found in all cells but which
The red blood cell of the dog - this protein is ubiquitous
298
What is the effect of transporting 3Na in to the cell for every Ca transported out
Cubes the Na concentration gradient
299
State the Henderson-Hasselbalch equation
Pka = Ph + log (HA/A-)
300
What is the orugh ph of the stomach
3
301
Define chemical antagonism
Substances that chemically alter agonists resulting in loss of function of the active drug
302
What is seen in first order clearance of a drug
Follows a mono-exponential decay model
303
What is meant by an electrogenic transport protein
The movement that occurs as a result of the transport proteins results in a net movement of charge
304
What class of enzymes are involved in drug metabolism and of which there are 57 genes for
Cytochrome P450 enxymes
305
Which member of the anion exchnger family involved in acid loading
Cl/HCO3 exchnager
306
How does the act of mast cells lead to an infla resp
Triggers Ca channel opening and iflux, causes degranulation and relase of histamine and tryptase and prod of PGS. Inc Ca --> act of NFkB transcribing pro infl genes
307
T/F
| Drugs for a particualr receptor can have the same EC50 but be unable to elicit a maximal response
T
308
Which method of drug adminsitration is quickest and used in emergency treatment
Intravenous
309
What activates store operated Ca channels
Depletion of Ca stores
310
What must drugs cross in order to be metabolised
PM
311
How do NSAIDS reduce oedema
PGs are vasodilators and so inhibit of PGs leads to decreased vasodilation and a decrease in BP reducing the hydrostatic pressure and fluid efflux from vessels
312
What other methods are used during a radiligand binding assay to preserve the ligand and binding site
Intro of protease inhibitors
313
Define pharmacokinetics
Study of how drugs are basorbed into the body, how they are distributed and eliminated
314
What are many drugs
Weak acids/bases
315
IC [HCO3-]
25 mM
316
What two factors determine lipid solubility
Partition coefficient and diffusivity diffusion constant
317
State nernst equation
61.54 log (ion-out / ion-in)
318
What is the role of the Na/H exchanger
Removes protons from the cell
319
Give an example of a kinase-linked receptor
Insulin receptor
320
What are the different families of receptor
Ligand-gated ion channels, GPCRs, kinase linked receptors and nuclear receptors
321
Mechanically operated Ca channles are found in many cells and respond to
Deformation
322
What must be true for drugs given orally
They must be resistant to being broken down by the gut
323
What is sig about the x intercept of a schild analysis
X-intercept is the affinity of the antagonist
324
Which type of cells mediate the IR in asthma, how is this different to rhu arth
Th2 mediate in astham, Th1 in rheu arth
325
Where might the ligand binding site of a GPCR be found
On EC surface - for peptides
| In pockets created by TM domains
326
Why are certain carriers referred to as secondary active
Facilitated transport protein that don't use ATP hydrolysis for transport but do use the electrochemical gradient set up by ATPases
327
Explain what is meant by enzyme induction and give an example
Expression of P450 enzymes for drugs can be influenced by other drugs as well as environmental factors
EG brussel sprouds - induce the expression of enzymes which increase alcohol metabolism
328
What do NSAIDS inhibit
Cyclooxygenase enzymes
329
Is the TAL perm to water and NH3
No impermeable to both
330
What is the effect of increased agonist concentration in a system which contains an antagonist which is outcompeting the agonist
Inc [agonist] - antagonist being out competed and less antagonism
331
What is transport of the Na/K ATPase a saturable function of
[Na]i
| [K]e
332
T/F - diffusion has a high uptake rate and no saturation point
F - it has a low uptake rate and no saturation point
333
What is the chemical name for aspirin
Acetylsalicyliic acid
334
Examples of medications taken via inhalation
Asthma med
| General anasthetics
335
Rough [A-] EC value
0 mM
336
What can be used in the short term to treat asthma
Salbuatmol B2 ad ag leads to relaxation of the smooth muscle in the airway leading to an inc radius of airway and inc in flow rate
337
Three types of Ca ATPases
Plasma membrane calcium pumps - pumps Ca out of the cell
Sarco/endoplasmic calcium pumps - Pump Ca out of the cytoplasm into organelles
Secretory pathway ca pumps - found on the golgi membrane - can also transport Mn2+
338
What does agonist binding reuslt in
Stabilising of the receptor conformation that facilitates signalling
339
What happens in phase II of small molecule drug metabolism
Enzymes carry out anabolic reactions that involve conjugation to produce an inactive product
Usuaully in large groups - i.e. sugar groups added to prevent absorption and further binding to receptors
340
What is the realationship between Kd and dissociation consant
A drug with a high affinity will have a low Kd value
341
What is significant about the drug conc which occupies 50% of the recepotrs
Equal to Kd
342
What are the two configurations that can be used in the patch clamp technique
Cell attached - record a few ions within a sealed region
Whole-cell - ruptured cell membrane allows recording of all ion channels in cell membrane
343
Example of a nuclear receptor
Examples of a ligand of a nucelar receptor
Steroid hormone R
Testosterone
Oestrogen
344
What is meant by the humaisation of Abs before they can be used in humans
Mod of Fc domain so AB isnt percieved as foreign by IS
345
pH equation
-log [H+]
346
IC [K]
100 mM
347
Is affinity a constant
Yes
348
The higher the receptor reserve the ...
Less drug required to cause the maximal response
349
What contributes to airway hyperactivity in asthma
Increased backgroud para activity leads to inc in basal tone and inc contraction in response in response to irritants
350
Main side effects of NSAIDS
Stomach pain, renal failulre, liver damage, bronchospasm
351
What must be done to the ligand for a radioligand binding assay to be performed
Radioactive labelled by tritiation or iodination with I125
352
How many TMDs does a ligand gated ion channel have
4
353
How do irreversible antagonists work
Form a covalent bond with the receptor
354
Which method of drug adminsitration is is often used for CNS drugs and how is this done
Intraethecal injection
| Drug into the CSF
355
What type of Ca signalling is found in secretory cells and nerve terminals and is activated by agonit bindning
Receptor operated ca channels
356
Which class or drugs can be passively absorbed and why
Lipid soluble drugs passively absorbed by moving through the plasma membrane of cells down their concentration gradient
357
A or P Suicide inhibitor
Aspirin
358
Explain how aspriirnin is eliminated from the body
In phase I the methylester group is replaced by a hydroxyl group converting acetylsalicyclic acid to salicyclic acid
Then in phase II a sugar group is added in a conjugation reaction that produces a glucuronide product
359
What is Na/H exchanger involved in
Acid extrusion
| NHE removes protons in exhcnage for Na (in)
360
What factors can influence the value of the set point to make the exchanger more active at a higher pH
Calcium calmodulin and protein kinase-C
361
How is the resting pH achieved
Resting when the rate of acid extrusion equals the rate of acid loading
362
What properties determine the effect of a drug in a living system
Efficacy affinity and specificity
363
How is that antibiotics are effective in treating meningitiis despite not being able to cross the BBB in the meninges
In patients with meningitis the blood brain barrier becomes leaky allowing for antibiotics to cross over and treat the infection
364
Approx Ek
-90mV
365
What factor influences the ammount of time you can spend spearating the unbound ligand
Kd - smaller the value the longer needed separating the unbound (as affinity is higher)
366
NAPQI
N-acetly-p-benzoquinone-imine
367
What are the main types of transport proteins
Carriers, channels and pumps
368
EC [HCO3-]
25 mM
369
State the general equation for acid disociation
HA --> H+ + A-
370
What is sig about COX1
Ubiquitously expressed and constitutively active
371
What domain do nuclear receptors have, what does this achieve
DNA binding domain, allows influence of transcription of genes
372
What is meant by the term ligand
Generic term for a small molecule or peptide that binds to a receptor and acts as an agonist or antagonist
373
What is seen in patients with asthma
Hyperactive airways resulting in bronchoconstriction and decreased radius of the bronchi
374
How is the equiptment used to measure pH in large cells calibrated
Electrodes and placed in pH standards and a graph of V against pH is plotted and gdt calculated
375
What are the main issues RE radioligands
PURITY - chemically pure, enantiomers filtered out
DEGRADATION - resolved by anti-oxidants and free radical scavenger
LABELLING - high specific activity needed at low tracer concentrations
