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Foundations - Me > Wk 4 - Receptor and ADME > Flashcards

Wk 4 - Receptor and ADME Flashcards

1
Q

What is pharmacokinetics?

A

The action that the body has on the drug

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2
Q

Pharmacodynamics?

A

The action that the drug has on the body

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3
Q

ADME

A

Absorption:
- Passage of drug from administration site to blood

Distribution:
- Passage of drug from blood to tissues

Metabolism/biotransformation:
- Chemical modification of drug to make more water soluble/excreted

Excretion:
- Passage of drug from blood to outside of body through urine

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4
Q

Passive diffusion

A
  • Driven by concentration gradient
  • Doesn’t require energy
  • Doesn’t saturate
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5
Q

G-protein coupled receptors

A
  • Most common drug receptor group
  • Generate 2º messenger to change cell function
    2º messengers: cAMP, Ca++, etc…
  • Drug binds to receptor coupled to G protein which does the effector function
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6
Q

What’s an orphan receptor?

A

When you don’t know what ligand the receptor binds to

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7
Q

Ligand-gated ion channels

A

Mechanism:

  1. Ligand binds
  2. Channel opens
  3. ions flow through and down gradient
  4. Depolarization of membrane
  5. Generation of action potential
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8
Q

Receptor direct binding/∆ gene transcription

A
  • Often associated with chaperone protein
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9
Q

Filtration transport

A
  • Doesn’t require ATP
  • Bulk flow of fluids through channel
  • Driving force = osmotic pressure difference
  • Move down gradient
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10
Q

Endocytosis transport

A
  • Requires ATP
  • Active bulk flow through membrane
  • Move in both directions
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11
Q

Facilitated diffusion

A
  • Carrier mediated
  • Doesn’t required ATP
  • Saturable
  • Selective
  • Moves down gradient
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12
Q

Active transport

A
  • Requires ATP
  • Carrier mediated
  • Saturable
  • Selective
  • Moves AGAINST gradient
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13
Q

What does Fick’s law describe?

A

FLUX!

FLUX = rate of transport = (permeability constant)(Cout-Cin)

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14
Q

What is bioavailability?

A

How much of a drug that’s administered to a patient is ABLE to move into circulating plasma

  • Fraction of total amount that could EVER get into circulation
  • 100% bioavailable? IV administration
  • Expressed from 0 –> 1
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15
Q

What should you take away from Lipinski’s rule of 5?

A
  • A compound with good bioavailability will be relatively small and MODERATELY lipophilic
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16
Q

Tissue perfusion rates (distribution)

A

It’s easy to diffuse into tissues that are highly perfused with blood

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17
Q

Plasma binding proteins (distribution)

A

High affinity??

More plasma binding protein and LESS DISTRIBUTION

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18
Q

Partitioning between plasma and tissues (distribution)

A

[ ] of drug between plasma and tissues not equal

Done via ion trapping, lipid solubilty, tissue binding protein

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19
Q

Volume of distribution

A

Fluid volume that would be required to contain the amount of drug present in the body at the same concentration as observed in the plasma

Vd = total amount of drug given/concentration of drug in plasma

The HIGHER the concentration in the plasma the LOWER the volume of distribution

Tells us about the relative distribution of the drug in the body

… Use body weight to normalize the Vd

20
Q

Variation of Vd (lipophilic/hydrophilic drugs)

A

Vd will be lower in fat people if it’s a lipid soluble drug

21
Q

Termination: Storage/redistribution

A
  • Drug can be trapped via redistribution and stuck in places where it shouldn’t be

Ex: anesthesia example
Works with 1st and 2nd pass distribution

22
Q

Termination: excretion/elimination

A

Kidney is major player

1º function: remove excess water soluble molecules from blood and return water

Filtration (through glomerular capillaries –> pre-urine)
Reabsorption (concentration gradient in collecting tubule and diffuses back out)
Secretion (selectively pull impounds from plasma and dump them in urine)

EXCRETION = FILTRATION - REABSORPTION + SECRETION

23
Q

Renal clearance (Clr)

A

Volume of plasma that’s cleared of drug by the kidney per hour

Clr = (CuVu)/Cp

GFR = glomerular filtration rate

24
Q

Renal clearance different types

A

No reabsorption/secretion? (filtered only)
GFR = Clr = 125mL/min

Filtered and reabsorbed
Clr < GFR (less getting out)

Filtered and secreted
Clr > GFR

25
Q

Biotransformation

A

In liver
Purpose: make compounds more polar so they can be more water soluble and excreted in the urine

  • Might be required to activate a drug from prodrug to drug

Phase I and II reactions often coupled but not required

26
Q

Biotransformation phase I reactions

A
  • Add/expose functional groups
  • Oxidation to make metabolites more polar/water soluble
  • Metabolites often become less active
  • MAJOR PLAYER = CYP450 - DO METABOLISM OF 75% OF DRUGS IN SER
27
Q

Biotransformation phase II reactions

A
  • Conjugation/synthesis reaction
  • Most common: glucuronidation
  • Usually results in inactivation
  • Can + large anionic groups to detoxify reactive electrophiles
  • SER
28
Q

Inhibitors of biotransformation

A
  • Inhibit CYP450 through competitive inhibition

- Non-microcosmal drug reaction like disulfiram reaction

29
Q

Drug occupancy theory and the 2 assumptions

A

Relationship between drug dose and effect (using law of mass action)

Assumptions:

  1. Effect is proportional to the receptor occupancy
  2. Interaction between drug and receptor is monovalent
30
Q

Agonist

A

Drug capable of inducing maximum response
Full efficacy
Alpha = 1

31
Q

Partial agonist

A

Drug is faction of the maximum that can be elicited overall
Partial efficiacy
1 > alpha > 0

32
Q

Antagonist

A

Drug can’t bind receptor and induces no response
Zero efficacy
Alpha = 0

33
Q

Affinity

A

Ability of drug to form complex with receptor
1/Kd
Greater affinity of drug for receptor the lower the [ ] of drug necessary to occupy receptor

34
Q

Efficacy

A

Capacity of drug/receptor complex to produce a response

35
Q

EC50

A

[ ] of a drug that produces 50% of maximal response

36
Q

Potency

A

COMPARATIVE TERM!

  • Doesn’t refer to maximal response
  • Will always be a ratio
37
Q

Competitive antagonism

A
  • Reversible
  • SLOPE STAYS THE SAME! (max response is same)
  • EC50 DECREASES
  • Graph shifts to the right
38
Q

Noncompetitive antagonism

A
  • Irreversible
  • Max response decreased
  • Affinity of agonist for receptor doesn’t ∆
  • Apparent # of receptors decreased
39
Q

Physiological antagonism

A
  • Can antagonize multiple pathways

Ex: insulin/glucocorticoids

40
Q

Inverse agonist

A
  • 2 state model theory
  • Does opposite of what normal agonist does
  • Binds inactive form to shift equilibrium to inactive form
  • Doesn’t follow occupancy theory because not necessarily monovalent
41
Q

Spare receptors

A
  • Small % of receptors to elicit max response

- EC50 and Kd values different — violation of occupancy theory

42
Q

Describe 2 state theory

A
  • Can be activated by agonists
  • Can be stopped by antagonist
  • Can be made inactive by inverse agonist
43
Q

Quantal log dose-response curve

A
  • All or nothing
  • Frequency distribution curve of response of population to a drug
  • Uses medan effective dose (ED50) = dose required to produce response in 50% of population
  • Helps judge drug potency
44
Q

Therapeutic index

A
  • Measure relative safety of a drug
  • Want it to be high
  • Ratio of LD50 – kill 50% of population:effective for 50% of population
45
Q

Certain safety factor

A
  • Ratio of death of 1% of population to therapeutic dose of 99% of population

Foundations - Me (10 decks)

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