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DDD x > Week 1 Part 2 > Flashcards

Week 1 Part 2 Flashcards

1
Q

What are some clinically useful partial agonist?

A
  1. Buprenorphine

2. Varenicline

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2
Q

Define ligand

A

any chemical which combines with a receptor

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3
Q

Ligand binds to recognition site of receptor

A
  1. agonist bind to recognition site

2. change conformation - opening/closing of relevant ion channel

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4
Q

What is the direction of ion movement dependent on?

A

concentration/electrochemical gradient

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5
Q

What happens to the target cell?

A

nature of the ion

not all ion channels are created equal

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6
Q

sodium floods in

A

depolarisation

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7
Q

chloride floods in

A

hyperpolarisation

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8
Q

Define affinity

A

Tenacity by which a drug binds to its receptor

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9
Q

What does ligands reside at?

A

minimal energy within a binding locus of a protein

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10
Q

What is the binding affinity influenced by?

A

non-covalent intermolecular interactions

e. g.
1. Hydrogen bonding
2. Electrostatic interactions
3. Hydrophobic and van der waal forces between 2 molecules

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11
Q

The higher the affinity

A

The lower this concentration will be

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12
Q

What is binding affinity measured and reported by?

A

Equilibrium dissociation

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13
Q

What is equilibrium dissociation used for?

A

Evaluate and rank order strengths of bimolecular interactions

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14
Q

The smaller the KD value

A

The greater the binding affinity of ligand for its target

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15
Q

What is KD?

A

a constant between free drug conc and free receptor conc

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16
Q

What happens if you increase the conc of drug?

A
  1. shift equilibrium over to right

2. increase in drug-receptor complex

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17
Q

What is the equation for KD?

A

Free drug [D] + unbound receptor [R] divided by drug-receptor associated complex [DR]

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18
Q

What yields a low KD value?

A

The numerator of equation will be low

The denominator will be high

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19
Q

Define antagonist

A

Blocks or dampens a biological response by binding to and blocking a receptor

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20
Q

Define agonist

A

A ligand that binds to receptor and alters receptor site - result in a biological response

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21
Q

What can receptor antagonist be?

A
  1. Competitive
  2. Non-competitive
  3. Reversible
  4. Irreversible
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22
Q

What is a reversible antagonist?

A

Binds non-covalently to the receptor

Can be washed out

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23
Q

What is irreversible antagonist

A

Bind covalently to the receptor and cannot be displaced by either competing ligands or washing

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24
Q

What is competitive antagonist?

A

Bind to the same site as agonist and blocks the agonists action

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25
Q

What is non-competitive antagonist?

A

Bind to allosteric site on the receptor to prevent activation of receptor

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26
Q

What is example of competitive antagonist?

A
  1. simple competitive e.g. nanitidine

2. Pseudo-irreversible slowly dissociating e.g. alosetron

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27
Q

What is example of non-competitive?

A
  1. Irreversible: chemically modifies receptor e.g. phenoxy-benzamine
  2. Allosteric e.g. b-carbolines (BDZ receptor)
  3. Functionl: acts as a second receptor
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28
Q

What are examples of clinically useful reversible competitive antagonist?

A
  1. Ondansetron
  2. Carvedilol
  3. Naloxone
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29
Q

What is used to block endogenous agonist?

A
  1. Ondansetron (Zofran)

2. Carvedilol (Eucardic)

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30
Q

What is Ondansetron?

A
  1. HT-3 receptor reversible competitive antagonist

2. inhibit vomitting

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31
Q

What is Carvedilol?

A
  1. Beta1 selective adrenoceptor reversible competive antagonist
  2. treatment of hypertension
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32
Q

What is used to block exogenous agonist?

A
  1. Naloxone
  2. opioid receptor competitive antagonist
  3. reverse opioid induced respiratory depression/overdose
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33
Q

What is EC50?

A

drug concentration producing 50% of a maximal effect

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34
Q

When is there an equilbrium?

A

Agonist and antagonist competing for a target site

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35
Q

What can restore agonist occupancy?

A

Raising agonist concentration

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36
Q

What happens when there is an increased agonist concentration?

A
  1. increase in fractional occupancy

2. magnitude of functional response is seen

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37
Q

What doesnt antagonist have?

A

efficacy

  • need a suitable agonist
  • action can be inhibited by the antagonist of interest
38
Q

What can antagonist potency be expressed in?

A

PA2 value

39
Q

Define PA2?

A

Negative logarithm of molar concentation of antagonist which will reduce the response of a tissue

40
Q

What is an advantage of non-competitive inhibitor?

A

Duration of action is dependent on the rate of turnover of receptor molecules

41
Q

What is disadvantage of non-competitive inhibitors?

A

Overdose

42
Q

What is H+/K+ ATPase?

A

Proton pump of the stomach

Exchanges H+ for K

43
Q

Where is H+/K+ ATPase found?

A

Apical membrane of parietal cells

44
Q

What is parietal cells?

A

Highly specialised epithelial cells located in inner lining of stomach called gastric mucosa

45
Q

How is H+/K+ ATPase activated?

A

Indirectly by gastrin that causes ECL cells to release histamine

46
Q

What does histamine do?

A

Bind to H2 receptors on the parietal cells

Activate CAMP-dependent pathway

47
Q

Where is K+ recycled from?

A

Canaliculus (small passageway) into the cytoplasm by K+ channels in apical membrane

48
Q

Describe mode of action of Omeprazole?

A
  1. Absorbed by GI tract into blood
  2. At PH7 omeprazole is not charged and can cross cell membrane
  3. In acid enviroment of secretory canaliculus - omeprazole is protonated and therefore trapped so concentration increases
  4. Omeprazole inactive on protonation converts to active sulfenamide - reacts convalently with H+/K+ ATPase and inhibits activity
  5. Resumption of acid secretion requires new synthesis of H+/K+ ATPase
  6. Half life of Omeprazole is ~18 hours
49
Q

What does G protein bind to?

A

guanine nucleotide GDP and GTP

50
Q

What are the 3 different subunits associated with inner surface of plasma membrane and transmembrane receptors?

A
  1. Ga
  2. GB
  3. GY
51
Q

What happens in the inactive state?

A

Ga has GDP in its binding site

52
Q

What happens when a hormone or other ligand bind to associated GPCR?

A

Allosteric change takes place in the receptor

causes allosteric change in Ga causing GDP to leave and be replaced by GTP

53
Q

What does GTP activate?

A

GA causing it to dissociate from GbGY

54
Q

What does activated Ga activate?

A

Effector molecule

55
Q

what does morphine mimic?

A

Endogenous enkephalin

56
Q

Define potency

A

The amount of drug required to produce a given effect

57
Q

Define efficacy

A

The degree to which an agonist evokes a cellular response

58
Q

What does intrinsic activity refer to?

A

Effect of agonist at the receptor itself, rather than overall effect on tissue

59
Q

Define EC50

A

the molar concentration of an agonist that produces 50% of maximal possible effect of that agonist

60
Q

Define pEC50

A

the negative logarithm to the base 10 of EC50 of an agonist

61
Q

What is pEC50 useful for?

A
  1. compare potencies of drugs

2. estimate margin of safety, relative to other actions of drug

62
Q

What does potency depend on?

A
  1. Drug factors - efficacy and affinity

2. System factors - receptor number and efficiency of coupling

63
Q

What can system factors cancel out?

A

Differences in drug factors

64
Q

What happens as the concentration of drug is increased?

A

Full agonist will go up to 100%

65
Q

What does partial agonist have?

A
  1. Affinity for receptor

2. Low efficacy

66
Q

What will partial agonist not produce?

A

maximum respinse

has efficacy of less than 1

67
Q

What can partial agonist reduce?

A

apparent Emax

68
Q

What are some examples of clinically useful partial agonist?

A
  1. Buprenorphine (Subutex)

2. Varenicline (Champix)

69
Q

What is Buprenorphine?

A
  1. Opioid receptor partial agonist
  2. produces pain relief with lower risk of respiratory depression
  3. used in situation of drug overdose and/or opioid abuse
70
Q

What is Varenicline?

A
  1. Alpha4/beta 2 selective nicotinic receptor partial agonist
  2. treat nicotine dependence
71
Q

What is inverse agonist?

A

Agent that binds to same receptor as agonist but induces a pharmacological response opposite to that of agonist

72
Q

What can the effect of inverse agonist be blocked by?

A

antagonist

73
Q

What must the receptor of inverse agonist have?

A

Constitutive activity in absence of ligand

74
Q

What does inverse agonist do?

A

Decrease the activity of a receptor below basal level

75
Q

What is the efficacy of inverse agonist?

A

<0%

76
Q

What does inverse agonist do?

A
  1. have higher affinity for the active state of receptor

2. shift the equilibrium back to inactive state

77
Q

What is constitutive activity?

A

A receptor which is capable of producing a biological response in the absence of bound ligand

78
Q

What is inverse agonist capable of doing?

A

Block constitutive activity of a receptor

79
Q

What is activation of G protein coupled receptors

A
  1. Activation of G proteins
  2. Receptor phosphorylation by GRKS
  3. B-arrestin migrates to receptor on activation
  4. leads to receptor internalisation into endosomes
  5. Internalised receptor/ B arrestin complex forms a scaffold MAP kinases to produce signal in cytosol
  6. Internalised receptor recycles to cell surface or degraded
80
Q

What is biased agonism?

A

Ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand

81
Q

When is functional selectivity present?

A

When a receptor has several possible signal transduction pathways

82
Q

Where is functional selectivity most extensively characterised?

A

GPCR

83
Q

What can receptors be seen to do?

A

Transverse an ‘‘energy landscape’

thermal energy drives the protein into preferred energy wells

84
Q

What happens when a molecule bind to receptor?

A

It becomes another thermodynamic species

85
Q

What are receptor confirmations?

A

Interconvertible

86
Q

What is Le Chatelier’s principle?

A

If a dynamic equilibrium is disturbed by changing the conditions, the position of equilibirum moves to counteract change

87
Q

What does a ligand enrich?

A

A particular confirmation that exist in accordance with thermal energy in system and proteins exist in ‘‘ensembles’’ of multiple conformations

88
Q

What does morphine do?

A

Activates the mu opioid receptor, a GPCR

89
Q

What is TRV130?

A

A G protein-biased ligand

elicits a robust G protein signalling with potency and efficacy similar to morphine

90
Q

What is TRV130 suggested to be?

A

Safer and more tolerable therapeutic for treating severe pain

DDD x (17 decks)

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