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1

What is the relationship between Kd and DR

Inverse

2

What does an agonist have to be able to do in order to be classed as a full agonist

Induce the max repsonse of the tissue

3

What can be said about the ion turnover of facilitated transport proteins

It is high
10^2 - 10^3 ions / s

4

what is the name of the transporter which allows Na to enter TAL cells

NKCC2

5

What type of cells are increase in rheu arth patients

Th1 cells

6

Does Kd always equal EC50

No

7

ADVANTAGE/DISADVANTAGE
H3 OR I(125)

Difficult to incorporate ligand fue to high mass

Disad I 125

8

What is occupancy dependent on

Drug concentration

9

What is meant by aspiring being a suicide inhibitor

Permanently binds to XOZ

10

ADVANTAGE/DISADVANTAGE
H3 OR I(125)

Biological act of the ligand can be reduced

Disad I 125

11

Act of macrophages as a result of autoimmune resp leads to synth of which two pro inf mediators

Interleukin-1 (IL-1) and tumor necrosis factor a (TNF-A)

12

What occurs when calcineurin is activated

Activation leads to removal of phosphate groups and act of TF NFKB that promotes transcription of pro-inflam chem/cytokines

13

NAPQI toxic intermediate A or P

Paracetamol

14

What is meant by physiological antagonism

When two or more drugs interact with opposing actions - or act through different transduction machinery

15

What is the difference between the nernst and goldman equations

Nernst used to calc eqbm pot wherease goldman used to calculate the membrane potential

16

Define specificity

the attribute that a drug will preferentially bind to one type of receptor over another

17

What can usually be said of the metabolism of a drug which is rapidly absorbed from the drug

Metabolism will be fast

18

Describe how allosteric modifications aid in acid extrusion

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

Give examples of medications given directly to the skin

Nicotine patches, chronic pain treatments such as fentinon

20

Who developed the patch clamp technique

Nehr and Sakman

21

ADVANTAGE/DISADVANTAGE
H3 OR I(125)

High specific activities can be obtained

Ad H3

22

Would a drug with a higher Kd be more or less potent

Less

23

How can we classify facilitated transport proteins

Uniporters, symporters and antiporters

24

What is the benefit of biologicals in treatment of autoimmune disease and how can this cause problems

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