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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
Extracellular domains of a ligand-gated channel bind to a _____.
ligand obvs
26
Explain the function and regulation of ligand-gated ion channels.
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
27
Ion channels are _____.
selective
28
Give 3 examples of ligand-gated channels? (specific to their ions)
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
29
What are voltage-gated ion channels activated by?
changes in electrical membrane potential
30
Where are voltage gated channels more likely to be found?
presynaptic
31
Where are ligand gated channels more likely to be found?
postsynaptic
32
Explain the presynaptic and postsynaptic channels using Ca2+ as an example
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)
33
Example of a voltage-gated Ca2+ channel
amplodipine (for high blood pressure)
34
Example of a voltage-gated Na+ channel
Phenytoin
35
Explain what an ion pump is
- 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)
36
Where are ion pumps located?
in cell membrane
37
What is the purpose of an ion pump?
to re-establish ion gradients
38
What are the 2 types of enzyme-linked receptors?
1 - cell membrane | 2 - intracellular
39
cell membrane enzyme-linked receptors are known as ____ _____ receptors
tyrosine kinase
40
Explain the structure of cell-membrane enzyme-linked receptors
- spans the membrane - extracellular domain binds to a LIGAND - intracellular domain has cytosolic enzyme activity which induces tyrosine phosphorylation
41
Explain the function and regulation of cell-membrane enzyme-linked receptors
- 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
Where are intracellular enzyme-linked receptors located?
in the cytoplasm
43
Describe the structure of an intracellular enzyme-linked receptor
-forms a heterodimer composed of an alpha and a beta subunit - contains an: - RD (regulatory domain) - CCD (coiled-coil domain) - CD (cyclase domain)
44
What are intracellular enzyme-linked receptors activated by?
nitric oxide (NO)
45
In intracellular enzyme-linked receptors: - NO activates initially - ultimately cGMP is activated In GPCR's: - receptor binding activates initially - ultimately cAMP is activated
ok man KNOW SLIDE 24 mini mechanism !!!
46
Intracellular receptors have two binding domains - what are they?
- ligand binding domain | - DNA binding domain
47
Where are intracellular receptors frequently located?
nucleus
48
Receptor ligands are ____ soluble?
lipid | so they can diffuse into the cell to interact with the nuclear receptor
49
Duration of action for: | ion channels
milliseconds
50
Duration of action for: | GPCR's (G protein coupled receptors)
seconds to minutes
51
Duration of action for: enzyme-linked receptors -guanylyl cyclase
seconds to minutes
52
Duration of action for: enzyme linked receptors -receptor tyrosine kinases
minutes to hours
53
Duration of action for: | -intracellular nuclear receptors
hours to days
54
see review slide (28 & 29)
okay man
55
Bmax
maximal specific binding of ligand to a receptor (top of normal graph) (plateau of log graph) *indicates the total concentration of receptor sites
56
Kd
eqbm dissociation constant between ligand and receptor *represents the concentration of drug at which half-maximal binding (50%) is observed
57
Affinity
ability of a drug to bind to a receptor
58
When Kd decreases, affinity ______
increases! | inverse relationship
59
Selectivity
degree to which a drug acts on a given site relative to other sites *describes preference for one receptor over the other
60
Emax
maximal effect induced by a drug (full agonist)
61
EC50
the concentration of drug producing an effect that is 50 perfect of the maximum
62
Potency
a measure of the amount of drug required to produce an effect of given magnitude
63
What is potency determined by?
EC50
64
EC50 and potency have an ____ relationship
INVERSE
65
higher EC50 = ____ potency
lower
66
Efficacy
measure of the ability of a drug to elicit a biological response by agonist
67
What is efficacy determined by?
Emax
68
Emax and efficacy have a ____ relationship
DIRECT
69
higher Emax = ____ efficacy
higher
70
When determining what drug is better - is efficacy or potency a better measure?
EFFICACY | -always look at efficacy and then potency
71
What is an agonist?
-mimics the action on the original endogenous ligand on the receptor
72
What are the 3 types of agonists?
full partial inverse
73
Agonists can be blocked by ______
antagonists
74
Define: full agonist
a drug that binds to a receptor and produces MAXIMAL biological response (that mimics response to endogenous ligand) *good efficacy
75
Define: partial agonist
- less than max - less than 100% -have affinity for receptor but have LOW EFFICACY
76
What happens when partial and full agonist are administered together?
partial agonist reduces the effects of the full agonist
77
Define: inverse agonists
- have affinity for the receptor but have negative effect | * exert opposite pharmacological effect of receptor agonist
78
What is the difference between an inverse agonist and an antagonist?
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
What are antagonists?
a drug that has affinity for the receptor but no efficacy ``` affinity = yes efficacy = no ```
80
T or F: an antagonist always a biological effect regardless of whether or not an agonist is present
FALSE MAN | -an antagonist has no biological effect if an agonist is not present
81
Describe the two mechanisms of competitive antagonists.
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
If competitive antagonist binds to same site - what happens?
no changes in Emax or efficacy -increase EC50 of agonist (decrease potency)
83
If competitive antagonist binds to different site - what happens?
decrease Emax (decrease efficacy) see slide 42 for summary
84
adverse effect
undesired or harmful effect resulting from a medication (drug)
85
What are 4 types of adverse effects?
- overdose (too much therapeutic effect) - poor tissue selectivity - poor receptor selectivity - drug interactions
86
How do we measure drug safety?
therapeutic index TD50 ED50
87
TD50
drug dose that produces a toxic effect or adverse effect in 50% of patients taking drug
88
ED50
drug dose that produces a therapeutic effect or desired response in 50% of patients taking drug
89
What is the difference between ED50 and EC50?
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
What ratio is used for therapeutic index (TI)
TD50/ED50
91
TI is high = ?
- therapeutic window is wide - safety is high - less adverse effects
92
high affinity + high selectivity = ??
high TI (therapeutic index)
93
Idiosyncratic
individuals exhibit an unusual drug response
94
Tachyphylaxis
an acute rapid loss of response to a drug (ex. pt took it yesterday, now today dose must be increased)
95
receptor desensitization
mechanism that reduces the receptor response to an agonist see slide 47 for examples
96
clinical trials are always done on ___
humans
97
Briefly describe the 4 phases of a clinical trial
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
SEE SUMMARY PAGE | slide 51 & 52
ok man

Pharmacology (21 decks)

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