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Block 1 Week 3 > Buxton: receptor theory > Flashcards

Buxton: receptor theory Flashcards

1
Q

main targets of drugs (4)

think TIER

A
  • -enzymes (aspirin, cyclooxygenase)
  • -transporters/carriers (prozac, serotonin reuptake transporter)
  • -ion channels (local anesthetics + Na+ channels)
  • -receptor proteins (cimethidine for histadine receptor)

(drug, target)

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2
Q

“receptor”

A

PROTEIN that participates in cellular communicatin via chemical signals

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3
Q

ligand

A

chemical signaling molecule that transmits signal to biochemical change in target

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4
Q

ligand examples (just throw a few out there)

A

drugs or hormones and NT

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5
Q

Receptor theory equation

A

D + R –> DR —> Effect

drug, receptor, drug-receptor complex

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6
Q

mass action

A

rate of RXN proportional to the product of concentration of reactants
JUST THINK LE CHATERLIER’S

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7
Q

hill langmuir equationa

A

[D] + [R] [DR]
k1=forward rxn
k-1= reverse rxn

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8
Q

Radioreceptor/radioligand binding assay

A

[receptor prep + radiolabeled drug + test drug] get put into test tube. then placed into a drug receptor complex, filtrated, and unbound drug or unbound radiolabeled drug get eluted off.

PURPOSE: figure out Kd/KA

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9
Q

kinetic experiment (radiolabeled)

A

look at K1 and K2 over time by looking at specific binding (counter per minute). K1 in mol/sec. k2 in sec.

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10
Q

total binding line

A

specific binding + non specific binding binding curves. add areas under curves

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11
Q

specific binding line

A

it’s linear and strong but then it tapers off, kinda looks the the Vmax line

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12
Q

non specific binding

A

binding to places OTHER than the THERAPEUTIC target. This line is linear so directly propertional to ligand added

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13
Q

Hyperbolic concentration binding curve

A

Drug concentration binding curve (x-axis) vs fraction of receptor bound [B] y axis.
Kd=when half of the receptors are bound (same thing as Ka)
Bmax = just Kmax but for binding (rectangular hyperbola).

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14
Q

Scatchard plot

A

specific binding/ free radioligand (y axis) vs specific binding (x axis).
B max is the x intercept
slope = -1/Kd
if specific binding, then LINEAR line

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15
Q

Hill-Langmuir equation

A

Background just to help out: Kd= k-1/k1; it’s a concentration. also known as dissociation constant.

Par = [D][[D] + Kd]]
where AR = DR
SUPER LEGIT TO FIGURE OUT PROPORTION OF DR/AR

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16
Q

log linear scale

A

y axis; fraction of receptor bound, B.
x axis: concentration in log scale.
overall: graph sigmoidal, and it’s easy to see the Kd; this means that drug is acting well

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17
Q

ED50
TD50
LD50

A 
therapeutic effect (dose)
toxic effect (dose)
lethal (dose)
at which 50 percent of ppl are affected
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18
Q

What’s the difference between graded concentration response curves and hyperbolic concentration binding curve?

A

y axis: %maximal response v fraction of bound

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19
Q

graded concentration response curve similarities to binding curve?

A

x axis: concentration in same units

GRAPH shape rectangular hyperbola in both

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20
Q

Quantal dose response curve

A

describe pop % responding rather than individual responses. in log scale and helps us identify best dosage

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21
Q

Full Agonist: two cases

A

max potency and MAX EFFECT

other case, reduced potency but MAX EFFECT

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22
Q

Partial Agonist

A

max potency but REDUCED EFFECT.

other casse, reduced potency but REDUCED effect

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23
Q

Potency

A

deterimined by concentration needed for effect

24
Q

What determines whether or not something is a full or partial agonist?

A

If the effect% is close to 100, then it’s full.

If effect% is low (close to 50%), then it’s partial

25
Q

Chemical antagonists

A

two drugs in solution that cancel each other out

26
Q

Physiological antagonists

A

two drugs that cancel each other out physiologically, like histamine and epinephrine

27
Q

Pharmacological antagonists

A 
Blockade of one DRUG RECEPTOR (but do not activate transduction cascade) by another compound, like propanolol blocking norepinephrine. 
Prevent agonist (drugs or hormones) from acting.
28
Q

Where do competitive antagonists bind?

A

they bind to same site on receptor as agonists!

29
Q

How can competitive antagonists be overcome?

A

by increasing agonist concentration, so it’s reversible

30
Q

Do competitive antagonists mainly affect potency or efficacy?

A

potency!

31
Q

Which are more clinically useful? Competitive or non competitive antagonists?

A

Competitive antagonists!!!

32
Q

Where do non-competitive antagonists bind?

A

They bind covalently and irreversibly to the agonist binding site OR to a site different to the agonist (reversibly or irreversibly)

33
Q

Can non-competitive antagonist inhibition be overcome by increasing agonist concentration?

A

NOPE coz we can’t get the agonist to compete for the same site

34
Q

Do non competitive antagonists mainly affect potency or efficacy?

A

Efficacy!!!

35
Q

concentration/dose response curves

A

Effect% v D:
linear scale: rectangular hyperbola
log-linear: totally sigmoidal; shows drug is acting well!

36
Q

Spare receptors appear commonly in the receptors for what ligands?

A

in receptors for hormones or NT

37
Q

ED50, TD50, LD50

A

concentrations at which half of individuals :
ED–have therapeutic effect
TD–have toxic effect
LD–have lethal effect

38
Q

Spare Receptors

A

pool of available receptors&raquo_space; # required for full response

39
Q

Explain spare receptor effect in relation to concentrations of D, R, and DR.

A

Sooo [R] goes up coz you got a greater pool of receptors; therefore, you don’t need as much [D] to reach same [DR] concentration!

40
Q

What’s the net effect of spare receptors?

A

Increased sensitivity to ligands

41
Q

What changes occur on the [D] vs receptor occupancy happen due to spare receptors?

A

Potency increases; so (ED50) value becomes smaller, but the max value of effect percentage is the same!

42
Q

Does response % increase linearly with receptor occupancy % WITHOUT spare receptors?

A

Yup. so biological effect is proportional to [DR] at all drug concentrations

43
Q

Does response % increase linearly with receptor occupancy % WITH spare receptors?

A

Biological effect is proportional to biological response % only in low concentrations up to ED50… HOWEVER it continues as a hyperbolic rectangle thereafter.

44
Q

How does effect of drug change when drug is given continuously or repeatedly?

A

It’s effect usually diminshies

45
Q

What’s tachiphylaxis?

A

A sudden decrease in response to drug after administration

46
Q

What causes receptor mediated drug desensitization? (2)

A
  1. loss of receptor FXN.

2. loss of receptor #

47
Q

What causes non-receptor mediated drug desensitization? (3)

A
  1. reduction of receptor-coupled signaling components.
  2. reduction of [Drug]
  3. physiological adaptation
48
Q

What’s the cause to lose receptor FXN and lose sensitivity?

and is this rapid or slow?

A
  • due to change in receptor CONFORMATION (like phosphorylation of Gprotein receptors).
  • usually part of cellular feedback mechanism

it’s a RAPID desensitization!

49
Q

What’s the cause to lose receptor NUMBER and then lose sensitivity?

and is this rapid or slow desensitization?

A
  • usually due to feedback effects of cell on agonist.
  • example: phosphorylation removes GPCR from cell surface.

IT’S LONG TERM!!!

50
Q

Therapeutic window

A

The relation of [Drug] to their therapeutic effects to and adverse effects in a population

51
Q

Full agonist

A

Drug can go two ways: Rinactive or Ractive. it chooses the active route and, therefore, increases response level!

52
Q

Partial agonist

A

Drug goes mainly to Ractive and, TO A LESSER EXTENT, Rinactive, so response level decreases a bit from partial agolist

53
Q

Inactive compound

A

Basal activity or drug goes to RI and Ra at same rate

54
Q

Inverse agonist

A

Drug goes to Ri and then level of response decreases a lot

55
Q

Do receptors mainly express the constitutive system or the native one?

A

Constitutive seems to be more important.

56
Q

Receptor antagonists FXN?

A

They DO NOT provoke a response in receptor cells; HOWEVER, they dampen the agonist activity.

57
Q

Agonist examples (prolly don’t need to know well)

A
  • Losartan for Hypertension
  • bisperidone for antipsychotic
  • -famotidine for hyperaciditicty

Block 1 Week 3 (10 decks)

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