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Pharmacology > Lecture 1 - Pharmacodynamics > Flashcards

Lecture 1 - Pharmacodynamics Flashcards

1
Q

What is a receptor?

A

A protein that interacts with drugs (ligands*) and imitates chain of events causing a form of cellular response.

(Proteins that can bind to drugs, hormones, neurotransmitters, cytokines, and other ligands)

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2
Q

List some examples of drug targets in cells?

A
  • G-protein coupled receptors
  • transort proteins
  • ion channels
  • tyrosine kinase receptor
  • intracellular enzymes
  • nuclear DNA

*drugs target these and then they activate or inhibit cellular functioning

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3
Q

Where can receptors be located? (3)

A
  • cell membrane
  • cytoplasm
  • nucleus
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4
Q

Explain v briefly how drugs trigger biological responses

A

Receptor-ligand bonding either activates or inhibits post-receptor signalling (a signal transduction cascade) and further triggers biological responses.

boom roasted

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5
Q

Does lipid-solubility matter when determining which receptors a drug can bind to?

A

Yes.

  • If lipid-soluble then it can penetrate the cell membrane and bind to receptors inside the cell membrane.
  • If not lipid-soluble - it cannot penetrate the cell membrane and will be forced to bind to receptors outside of the cell membrane.
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6
Q

Receptors are ____ for drugs.

A

Targets

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7
Q

What determines the quantitative relation between the conc of a drug and it’s biological effect?

A

receptors man

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8
Q

What properties effect the relationship between drug dose and the pharmacologic response?

A

potency
efficacy
agonists
antagonists

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9
Q

T or F: receptors determine both the therapeutic and toxic effects of drugs in pts

A

true

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10
Q

List the 4 receptor families

A

1-G protein-coupled receptors (GPCRs)
2-ion channels
3-enzyme-linked receptors
4-Intracellular receptors

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11
Q

What receptor type is the biggest family of receptors and 30% of drugs act on members of this family.

A

GPCRs

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12
Q

What are the most common site of drug action – most targeted by drugs?

A

GPCRs

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13
Q

Describe the structure of the receptor

A
  • single alpha helical peptide with 7 transmembrane domain

- extracellular domain contains the ligand-binding area

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14
Q

a G protein has 2 subunits - what are they?

A
  • alpha

- beta gamma

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15
Q

What are the 3 different isoforms of the alpha subunit?

A

G - alpha stimulatory
G - alpha inhibitory
Gq

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16
Q

What two things can alpha subunit bind to?

A
  • GDP

- GTP

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17
Q

What does the beta gamma subunit inhibit?

A

It inhibits the alpha subunit.

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18
Q

Describe v briefly the function and regulation of GPCRs

A

1 - unoccupied receptor doesn’t bind with G protein
2 - occupied (by a hormone or neurotransmitter) receptor changes shape and interacts with the G protein and G protein releases GDP and binds with GTP.
3 - alpha subunit of G protein dissociates and activates adenylyl cyclase
4 - hormone or neurotransmitter is now not present and the receptor reverts back to it’s resting state, GTP on the alpha subunit is hydrolyzed back to GDP, and adenylyl cyclase is deactivated

**see slide 12

**this also affects second messengers

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19
Q

Give some examples of second messengers

A

cAMP (cyclic adenosine monophosphate)
IP3 (inositol-1,4,5 triphosphate)
DAG (diacylglycerol)
Calcium

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20
Q

What 2 things are activated by GPCRs?

A

AC (adenylyl cyclase)

PLC (phospholipase C)

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21
Q

MEMORIZE SLIDE 13

A

OK MAN

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22
Q

What ions are more abundant outside of the cell?

A

Na+
Ca2+
Cl-

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23
Q

What ions are more abundant inside of the cell?

A

A-protein

K+

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24
Q

What are the 2 types of ion channels?

A
  • ligand gated

- voltage gated

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25
Q

Extracellular domains of a ligand-gated channel bind to a _____.

A

ligand obvs

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26
Q

Explain the function and regulation of ligand-gated ion channels.

A

when the ligand binds to the channel - it triggers a conformational change in the receptor and then the channel opens

*direction of movement determined by electrochemical gradient

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27
Q

Ion channels are _____.

A

selective

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28
Q

Give 3 examples of ligand-gated channels? (specific to their ions)

A

1 - nicotinic ACh receptor
(ligand-gated Na+ channel)

2 - glutamate N-methyl-D-aspartate (NMDA) receptor
(ligand-gated Ca2+ channel)

3 - Gamma-aminobutyric acid (GABA) receptor
(ligand-gated Cl- channel)

*slide 18 for more details

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29
Q

What are voltage-gated ion channels activated by?

A

changes in electrical membrane potential

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30
Q

Where are voltage gated channels more likely to be found?

A

presynaptic

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31
Q

Where are ligand gated channels more likely to be found?

A

postsynaptic

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32
Q

Explain the presynaptic and postsynaptic channels using Ca2+ as an example

A

presynaptic (voltage gated channel) - activation of neurotransmitter release

postsynaptic (ligand gated channel) - activation of calcium dependent enzymes (because calcium is now present and able to activate other enzymes and trigger a biological response)

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33
Q

Example of a voltage-gated Ca2+ channel

A

amplodipine (for high blood pressure)

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34
Q

Example of a voltage-gated Na+ channel

A

Phenytoin

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35
Q

Explain what an ion pump is

A
  • it’s a transmembrane protein that moves ion though a plasma membrane AGAINST their concentration gradient (low to high conc) (i.e. uses energy)
  • ion channels move ions with the concentration gradient (high to low)
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36
Q

Where are ion pumps located?

A

in cell membrane

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37
Q

What is the purpose of an ion pump?

A

to re-establish ion gradients

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38
Q

What are the 2 types of enzyme-linked receptors?

A

1 - cell membrane

2 - intracellular

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39
Q

cell membrane enzyme-linked receptors are known as ____ _____ receptors

A

tyrosine kinase

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40
Q

Explain the structure of cell-membrane enzyme-linked receptors

A
  • spans the membrane
  • extracellular domain binds to a LIGAND
  • intracellular domain has cytosolic enzyme activity which induces tyrosine phosphorylation
41
Q

Explain the function and regulation of cell-membrane enzyme-linked receptors

A
  • ligand binding = conformational change
  • forms dimers
  • converts kinases from inactive forms to active forms
  • induces receptor tyrosine auto-phosphorylation
  • recruit protein targets
  • metabolism, growth and differentiation are controlled by these types of receptors (cell-membrane enzyme-linked receptors)
42
Q

Where are intracellular enzyme-linked receptors located?

A

in the cytoplasm

43
Q

Describe the structure of an intracellular enzyme-linked receptor

A

-forms a heterodimer composed of an alpha and a beta subunit

  • contains an:
  • RD (regulatory domain)
  • CCD (coiled-coil domain)
  • CD (cyclase domain)
44
Q

What are intracellular enzyme-linked receptors activated by?

A

nitric oxide (NO)

45
Q

In intracellular enzyme-linked receptors:

  • NO activates initially
  • ultimately cGMP is activated

In GPCR’s:

  • receptor binding activates initially
  • ultimately cAMP is activated
A

ok man

KNOW SLIDE 24 mini mechanism !!!

46
Q

Intracellular receptors have two binding domains - what are they?

A
  • ligand binding domain

- DNA binding domain

47
Q

Where are intracellular receptors frequently located?

A

nucleus

48
Q

Receptor ligands are ____ soluble?

A

lipid

so they can diffuse into the cell to interact with the nuclear receptor

49
Q

Duration of action for:

ion channels

A

milliseconds

50
Q

Duration of action for:

GPCR’s (G protein coupled receptors)

A

seconds to minutes

51
Q

Duration of action for:
enzyme-linked receptors
-guanylyl cyclase

A

seconds to minutes

52
Q

Duration of action for:
enzyme linked receptors
-receptor tyrosine kinases

A

minutes to hours

53
Q

Duration of action for:

-intracellular nuclear receptors

A

hours to days

54
Q

see review slide (28 & 29)

A

okay man

55
Q

Bmax

A

maximal specific binding of ligand to a receptor
(top of normal graph)
(plateau of log graph)

*indicates the total concentration of receptor sites

56
Q

Kd

A

eqbm dissociation constant between ligand and receptor

*represents the concentration of drug at which half-maximal binding (50%) is observed

57
Q

Affinity

A

ability of a drug to bind to a receptor

58
Q

When Kd decreases, affinity ______

A

increases!

inverse relationship

59
Q

Selectivity

A

degree to which a drug acts on a given site relative to other sites

*describes preference for one receptor over the other

60
Q

Emax

A

maximal effect induced by a drug (full agonist)

61
Q

EC50

A

the concentration of drug producing an effect that is 50 perfect of the maximum

62
Q

Potency

A

a measure of the amount of drug required to produce an effect of given magnitude

63
Q

What is potency determined by?

A

EC50

64
Q

EC50 and potency have an ____ relationship

A

INVERSE

65
Q

higher EC50 = ____ potency

A

lower

66
Q

Efficacy

A

measure of the ability of a drug to elicit a biological response by agonist

67
Q

What is efficacy determined by?

A

Emax

68
Q

Emax and efficacy have a ____ relationship

A

DIRECT

69
Q

higher Emax = ____ efficacy

A

higher

70
Q

When determining what drug is better - is efficacy or potency a better measure?

A

EFFICACY

-always look at efficacy and then potency

71
Q

What is an agonist?

A

-mimics the action on the original endogenous ligand on the receptor

72
Q

What are the 3 types of agonists?

A

full
partial
inverse

73
Q

Agonists can be blocked by ______

A

antagonists

74
Q

Define: full agonist

A

a drug that binds to a receptor and produces MAXIMAL biological response (that mimics response to endogenous ligand)

*good efficacy

75
Q

Define: partial agonist

A
  • less than max
  • less than 100%

-have affinity for receptor but have LOW EFFICACY

76
Q

What happens when partial and full agonist are administered together?

A

partial agonist reduces the effects of the full agonist

77
Q

Define: inverse agonists

A
  • have affinity for the receptor but have negative effect

* exert opposite pharmacological effect of receptor agonist

78
Q

What is the difference between an inverse agonist and an antagonist?

A

Antagonist - fails to produce a biologic response

Inverse Agonist - produces a biologic response/pharmacological effect but in the exact opposite form of what is desired

79
Q

What are antagonists?

A

a drug that has affinity for the receptor but no efficacy

affinity = yes
efficacy = no
80
Q

T or F: an antagonist always a biological effect regardless of whether or not an agonist is present

A

FALSE MAN

-an antagonist has no biological effect if an agonist is not present

81
Q

Describe the two mechanisms of competitive antagonists.

A

they bind to the same site on the receptor with the agonist

-they prevent an agonist from binding to its receptor

OR

  • they bind to an allosteric site (other than the agonist-binding site)
  • which prevents the receptor from being activated even if the agonist is attached to the active site
82
Q

If competitive antagonist binds to same site - what happens?

A

no changes in Emax or efficacy

-increase EC50 of agonist (decrease potency)

83
Q

If competitive antagonist binds to different site - what happens?

A

decrease Emax (decrease efficacy)

see slide 42 for summary

84
Q

adverse effect

A

undesired or harmful effect resulting from a medication (drug)

85
Q

What are 4 types of adverse effects?

A
  • overdose (too much therapeutic effect)
  • poor tissue selectivity
  • poor receptor selectivity
  • drug interactions
86
Q

How do we measure drug safety?

A

therapeutic index

TD50
ED50

87
Q

TD50

A

drug dose that produces a toxic effect or adverse effect in 50% of patients taking drug

88
Q

ED50

A

drug dose that produces a therapeutic effect or desired response in 50% of patients taking drug

89
Q

What is the difference between ED50 and EC50?

A

ED50 - drug dose that produces therapeutic effect in 50% of Pt’s taking drug

EC50 - concentration of drug producing an effect that is 50% of the maximum

90
Q

What ratio is used for therapeutic index (TI)

A

TD50/ED50

91
Q

TI is high = ?

A
  • therapeutic window is wide
  • safety is high
  • less adverse effects
92
Q

high affinity + high selectivity = ??

A

high TI (therapeutic index)

93
Q

Idiosyncratic

A

individuals exhibit an unusual drug response

94
Q

Tachyphylaxis

A

an acute rapid loss of response to a drug (ex. pt took it yesterday, now today dose must be increased)

95
Q

receptor desensitization

A

mechanism that reduces the receptor response to an agonist

see slide 47 for examples

96
Q

clinical trials are always done on ___

A

humans

97
Q

Briefly describe the 4 phases of a clinical trial

A

1 - for safety

  • small number of healthy volunteers (20-100)
  • find max tolerated dose

2 - (100-200)
-identify therapeutic dose and study efficacy

3-larger # of pt’s
-further establish and confirm safety and efficacy

4 - large # of pt’s

  • post marketing studies
  • monitor safety of new drug
  • safety studies during sales
98
Q

SEE SUMMARY PAGE

slide 51 & 52

A

ok man

Pharmacology (21 decks)

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