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Pharm Exam 1 > Podgorski - Dose Response Curves > Flashcards

Podgorski - Dose Response Curves Flashcards

1
Q

Pharmacokinetics

A

How factors affect the conc. of drug at active site as a function of time

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2
Q

Pharmacokinetic processes

A

ADME - absorption, distribution, metabolism, excretion

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3
Q

Pharmacodynamics

A

How target cells respond to delivered conc. of drug

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4
Q

Majority of drug receptors:

Drugs:

A

Cell-surface signaling protein. Bind NT/hormones

Proteins

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5
Q

Basic mechs of transmembrane signalling

A
  1. Lipid-soluble ligand
  2. Transmembrane receptor protein
  3. Transmembrane receptor
  4. Ligand-gated ion channel
  5. G-protein coupled receptor – production of intracellular second messengers
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6
Q

Transmembrane receptor protein

A

Its activity regulated allosterically by a

ligand binding to extracellular domain

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7
Q

Lipid-soluble ligand

A

Acts on intracellular receptor

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8
Q

Transmembrane receptor

A

Binds and stimulates protein tyrosine kinase

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9
Q

Ligand-gated ion channel

A

Opening and closing regulated by ligand binding

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10
Q

G-protein coupled receptor

A

Production of intracellular second messengers

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11
Q

Receptor Properties (3)

A
  1. Determine the quantitative relations between dose or
    concentration of drug and pharmacologic effects
  2. Determine drug selectivity of action (depending on
    molecular size, shape, and electrical charge of a drug)
  3. Mediate the actions of pharmacologic agonists and
    antagonists.
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12
Q

Drug receptor vs. target

A

Phospholipids, gangliosides, channel proteins, intracellular enzymes, DNA = Targets

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13
Q

Lipid Soluble Drugs:

Enzymes
Transcription factors
Structural proteins

A

Enzymes: alter production of metabolic molecule (vit k and coagulase cascade)

TFs: steroids and thyroid hormone

SPs: antimitotic vinca alkaloids

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14
Q

Glucocorticoid receptor action

Act by:
Lag period:
Persists:

A

Act by regulating gene expression

Lag period of 30 min to several hours

persisting effects – hours or days

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15
Q

Transmembrane enzyme receptors:

Extracellular vs intracellular

A

extracellular hormone-binding domain

intracellular enzyme domain

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16
Q

Transmembrane enzyme receptors:

Mediate first steps in:

A

insulin, EGF, PDGF, ANP, and TGFb signaling

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17
Q

Transmembrane enzyme receptors intensity and duration regulated by:

A

receptor downregulation

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18
Q

Transmembrane enzyme receptors:

examples:

A 
monoclonal antibodies (trastuzumab,
cetuximab); small molecule inhibitors (gefitinib, erlotinib)
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19
Q

Source of protein kinase activity in cytokine receptors:

A

Jak kinases (not intrinsic)

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20
Q

Cytokine receptors examples:

A

Ligands include growth hormone, erythropoietin, several kinds of interferon; mechanism closely related to RTKs

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21
Q

LIGAND-GATED CHANNELS Mimic action of:

A 
endogenous ligands (acetylcholine,
serotonin, GABA, glutamate)
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22
Q

LIGAND-GATED CHANNELS Transmit signal across plasma membrane by:

A

Transmit signal across plasma membrane by increasing transmembrane conductance and changing membrane potential

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23
Q

LIGAND-GATED CHANNELS regulated by:

A 
multiple mechanisms (e.g. phosphorylation
and endocytosis)
24
Q

LIGAND-GATED CHANNELS response time:

A

rapid (milliseconds)

25
Q

Voltage gated channels are controlled by:

A

membrane potential

26
Q

Voltage gated channels ex:

A

verapamil (voltage-gated calcium channel). anti arrhytmic effects through actions on voltage-gated calcium channels.

remember, both ligand and voltage-gated channels have very fast response times (millliseconds)

27
Q

Examples of ligand-gated receptor:

A

Nicotinic acetylcholine (ACh) R

28
Q

G-protein coupled receptors,

mech

A

second messengers

29
Q

G-protein coupled receptors,

examples

A

Biggest group

beta-adrenoreceptors, glucagon receptors, thyrotropin receptors, subtypes of DA and 5HT Rs

30
Q

2nd messenger activation: adenylyl cyclase

type of response:
acts via:
response

A

Hormonal responses

Acts via stimulation of cAMP-dependent
neurotransmitters, growth factors
protein kinases

Response: increase or decrease in cAMP

31
Q

2nd messenger activation: Phospholipase C

triggered by:
acts via:
response:

A

Triggered by hormones, neurotransmitters,
growth factors

  • Acts via binding to GPCR (G Protein-Coupled Receptors) or RTKs (receptor tyrosine kinase)
  • Response: increase in IP3, DAG
32
Q

Mass action

A

increasing ligand conc. produces more binding

controls binding of ligands to receptor

33
Q

Kd =

A

Equilibrium dissociation constant

conc. at which 50% of receptors or occupied

Kd = [D][R]/ [DR] = Koff/Kon

D= free drug
R= free receptor
DR= drug-receptor complex
34
Q

Kd at equilibrium =

A

[D][R] Kon = [DR] Koff

35
Q

Why do the binding and response curves look identical?

A

assume response is directly proportional to the amount of drug-receptor complex that is formed.

36
Q

How is drug-receptor binding like enzyme kinetics?

A

Response ~ velocity

Kd ~ km

37
Q

Response/response max =

A

[DR]/[R]t = [D]/[D] + Kd

38
Q

Agonist definition

A

binds to a receptor and stabilizes

it in a particular conformation

39
Q

Efficacy def:

A

measure of max response (height on curve)

40
Q

EC50 def:

A

conc. req. for 50% of the max response

41
Q

Potency def:

A

comparison of EC50s.
More potency = less conc. needed for response
(The one closer to the left has higher potency)

42
Q

Antagonist def:

A

An agent that binds to a receptor but cannot produce the conformational change
necessary to trigger the downstream events.

43
Q

Response when antagonist binds by itself:

A

None; binds but can’t produce the conformational change necessary to trigger downstream events

44
Q

Competitive vs noncompetitive antagonists

A

competitive: reversible
non: irreversible

45
Q

effects of competitive antagonists on chart:

A

Apparent Kd for the agonist increases

Shifts to the right (higher conc. needed for same response)

No effect on efficacy

46
Q

NC antagonist binds:

effect on efficacy

A

binds to active or allosteric site of the receptor (downstream effects)

This cannot be overcome by increasing agonist
concentrations

reduces efficacy

47
Q

Non competitive antagonist summary

effect on affinity and potency

A

As the noncompetitive inhibitor conc.increases, the apparent efficacy decreases since the inhibitor inactivates receptors or downstream effectors.

no effect on apparent affinity (Kd) for pure noncompetitive antagonists

potency is not affected

48
Q

Physiological antagonism:

Exs:

A

Caused by agonist and antagonist acting at two independent sites and inducing independent, but opposite effects

Exs: glucocorticoid hormones and insulin)

49
Q

Chemical antagonism:

Exs:

A

Caused by combination of agonist with antagonist, with resulting inactivation of the agonist

(e.g., dimercaprol and mercuric ion; heparin and protamine)

50
Q

Inverse agonist

A

Inverse agonist produces effect opposite to the effect of agonist

51
Q

Which of the following terms best describes a drug that blocks the action of epi at its vascular alpha receptors by occupying the epi receptor binding sites without activating them?

A

Non-competitive antagonists

52
Q

What best describes an antagonist that interacts directly with the agonist and not at all, or only incidentally with the receptor?

A

Chemical antagonist

53
Q

“Spare receptors”

What pathway?

Effects?

common for:

linked to:

A

alpha 1 adrenergic pathway

full response with less than 100%
receptor occupancy

common for hormone receptors and
neurotransmiiters

true for receptors linked to enzymatic
signal transduction cascades

54
Q

Mechanism of spare receptor:

Results:

A

receptor remains activated after the agonist departs, allowing one agonist molecule to activate several receptors

cell signaling pathways allow for significant amplification of relatively small
signal, and activation of only few receptors produces maximal response

result: high sensitivity with fast turn-off

55
Q

Receptor regulation:

A

Rapid desensitization

Resensitization

Downregulation

56
Q

congeners of ACh

Analog of ACh

A

congeners of ACh: propionylcholine and butyrylcholine

Analog of ACh: acetylthiocholine

Pharm Exam 1 (23 decks)

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