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DDD x > Week 3 Part 1 > Flashcards

Week 3 Part 1 Flashcards

1
Q

What are ideal drug like properties?

A
  1. Potency and selectivity vs. Target
  2. Dissolution and permeation through the GI tract
  3. Metabolic stability - good oral bioavailability and duration of action
  4. Absence/non-impact of dose/time dependent pk effects
  5. Able to be co-prescribed without complicated dosage adjustments
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2
Q

Cimetidine

A

First selective H2 Antagonist
Good compound - it worked
It had potent selectivity vs target
Oral drug - dissolution of permeation through the GIT
It has metabolic stability
Good oral bioavailability and duration of action
High dose significant risk of drug dose interaction

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3
Q

What is very important in pharmacokinetics?

A

Duration of action

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4
Q

What is ideal for a drug?

A

Short acting drug with anaesthetics properties

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5
Q

What do people vary in?

A
  1. Appearance and philosophy
  2. Physiology and biochemistry
  3. Occupations and habits
  4. Genetics - genotype vs phenotype
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6
Q

What does source of variability start of with?

A
  1. Compliance and comprehension
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7
Q

Give an example of source of variability

A
  1. Drug in tablet
  2. Drug in tablet in gut
  3. Drug in gut
  4. Drug in blood
  5. Drug in tissues
  6. Drug at receptor
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8
Q

What is source of variability

A
  1. Compliance/comprehension
  2. Release
  3. Absorption
  4. Distribution
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9
Q

What is a desired response?

A

Drug at receptor

Therapy

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10
Q

What does ADME stand for?

A
  1. Absorption
  2. Distribution
  3. Metabolism
  4. Elimination
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11
Q

What is Absorption?

A

All processes from the site of administration to the site of measurement

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12
Q

What is Distribution?

A

The reversible transfer of drug between the site of measurement and other sites within the body

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13
Q

What is metabolism?

A

The irreversible loss of drug from the body by biochemical conversion

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14
Q

Elimination

A

The irreversible loss of drug from the site of measurement within the body

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15
Q

What is excretion?

A

The irreversible loss of drug from the body

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16
Q

What is disposition

A

Elimination (clearance) + distribution

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17
Q

What is the ADME process?

A

Take drug orally
Absorbed across the gut wall
The gut is efficient with metabolism and drug transporters
It then hits the liver

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18
Q

What are the ADME questions?

A
  1. Is the drug absorbed by mouth?
  2. Which organs are exposed to the drug?
  3. How long does the drug stay in the body?
  4. How is the drug removed from the body?
  5. What factors influence drug handling?
  6. What is the appropriate route of administration?
  7. How should the drug be formulated?
  8. What are the appropriate doses and dose regimens?
  9. Which drug interactions are likely to be important?
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19
Q

How is the drug removed from the body?

A

Unchanged

Metabolites

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20
Q

What factors influence drug handling?

A

Physiological
Pathological
Pharmaceutical
Pharmacological

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21
Q

What are the appropriate doses and dose regimens?

A
  1. Animal studies (pharmacology and toxicology)

2. Patients

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22
Q

What is pharmacokinetics?

A

Forcing function behind pharmacodynamics

Seeks to provide a mathematical basis for the description of the time course of drugs (and their metabolites) in the body

Refers to the quantitiative study of the process of ADME

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23
Q

What is the purpose of pharmacokinetic (PK)?

A

Get a handle on where you think your therapeutic index/ window is

Maximum tolerated conc (MTC) vs a minimum effective conc (MEC)

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24
Q

What are the pharmacokinetic terms?

A

C-Max —> max conc
T-Max —> time at which max conc occurs

Half life (mean residence time (MRT)) - how often of the dosing regimen

Clearance and absorption - what happens between site of administration and blood sample

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25
Q

What are the key driving parameters behind half life?

A
  1. Volume of distribution
  2. Clearance
  3. Bioavailability
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26
Q

Why is clearance important pharmacokinetic parameter?

A

Defines how much of the dose that you have to give initially and how long does that dose stay in the body

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27
Q

What is bioavailability?

A

Study of the factors which influence and determine the amount of intact drug which gets from the site of administration to the site of action/measurement and the rate at which it gets there

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28
Q

What is absolute bioavailability?

A

A measure of the proportion of intact drug reaching the systemic circulation following extravascular administration compared with an intravenous dose

Cannot be > 1 (non-linear)
Low F = large variability

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29
Q

Absolute bioavailability

A

Ratio between what I take by mouth vs what’s the area of the curve following direct administration into the vein since all the drugs has done into the vein

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30
Q

The lower the oral bioavailability

A

The higher the variability

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31
Q

What is the benefit of a lower bioavailability drug?

A

We try to screen out the compounds earlier on in the drug discovery

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32
Q

What is the calculation for absolute bioavailability?

A

The ratio under the area of the curve following oral administration divided by area under curve following intravenous administration corrected for the doses

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33
Q

What is clearance?

A

Proportionality factor linking drug concentration in the blood (or plasma) to the rate of drug elimination

Flow parameter constant throughout the time interval

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34
Q

Intravenous administration

A

Distribute instantaneously in the whole of the body

All of the drug is distributed to the rest of the body before reaching the liver

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35
Q

Oral dose/administration

A

Has to go through the liver first
You get extraction/clearance across the liver

All of the drug must first pass through the liver before it reaches the rest of body

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36
Q

What is drug clearance?

A

The measurement of the volume of blood/plasma from which a substance is irreversibly removed per unit time

I.e. the rate of drug removal

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37
Q

What is rate constant?

A

Constant fraction per unit time

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38
Q

For hepatic clearance, you have an extraction rate across the liver, what is it?

A

Blood flow x difference in arterial and venous

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39
Q

What can the extraction ratio vary between?

A

0 - where no drug is eliminated

1 - where all the drug is eliminated in the liver

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40
Q

If you want a drug with good oral

Bioavailability

A

You want a low extraction ratio

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41
Q

What can extraction also be?

A

Metabolism

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42
Q

What do most oral drugs have?

A

Low extraction ratio

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43
Q

What is the equation for extraction ratio?

A

Rate of extraction/ Rate of presentation

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44
Q

Drugs with E > 0.7

A

High extraction ratio

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45
Q

Drugs < 0.3

A

Low extraction ratio

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46
Q

What does clearance relate to?

A

Product of organ blood flow to the extraction ratio

Represents the volume of blood that is irreversibly cleared per unit time

47
Q

Renal clearance

A

Drug comes out the urine

48
Q

CLt = (F.Dose)/AUC

A

F = intravenous always 1

49
Q

What do people working in the drug discovery always look at?

A

The relationship of clearance to liver blood flow

50
Q

What is the cause of low oBA and low clearance?

A

It doesn’t have permeation across GIT

51
Q

Use of 70/30 rule

A

High > 70% of reference
Low < 30% of reference
Moderate 30-70%

52
Q

The amount of the drug in the tissue

A

Function of the volume of tissue
Concentration of the tissue
Partition co-efficient

53
Q

What is available for distribution?

A

Small molecules bind to proteins

Inbound concentration is available for distribution

54
Q

Amount of drug in the tissue

A

VT . CT . Kip

VT = volume of tissue 
CT = tissue concentration 
KP = tissue:blood partition coefficient (CT/CV)
55
Q

What key site do you look for in toxicology?

A

Adrenals

Small amount of tissue which has a very High blood flow rate

56
Q

The lower the perfusion

A

The larger the tissue

The poorer tissue distribution

57
Q

What is distribution dependent on?

A
  1. Affinity of drug for tissue (kp)
  2. Blood flow to the tissue
  3. Tissue size
58
Q

What is volume of distribution?

A

relates to the amount of drug in the body at any one time to the amount at the measured site (blood/plasma)

Effectively a dilution factor

59
Q

Initial distribution volume (Vd)

A

Volume of the space that the drug equilibrates with instantaneously

60
Q

Volume of distribution based on terminal half life (Vdb)

A

volume of space associated with terminal phase

61
Q

What is steady-state volume of distribution (Vss)

A

Volume of space that the drug occupies at steady-state

62
Q

What is hypothetical value of volume of distribution?

A
  1. Totally body water = 42 L/70kg man
  2. Extracellular fluid = 20% body weight
  3. Plasma volume = 3 L/70kg man
  4. Blood volume = 5L/70kg man
63
Q

What does the volume of distribution not tell?

A

Where the drug is

But it tells you where it isn’t

64
Q

What is terminal half life?

A

Time taken for the drug concentration to decline to half its original value

65
Q

Whatever drug you take

A

It will never disappear

There will always be a tiny amount

66
Q

Clearance, volume and half life

A

Cl = K x V

67
Q

If you want to increase half life

A

Reduce the clearance

68
Q

What can some drugs bind to?

A

Plasma proteins
Can be species specific

Reversible and rapid process
- can be associated with idiosyncratic toxicity

69
Q

What is drug-protein complex?

A

Large

Only unbound is available for distribution

70
Q

What is an important determinant in drug distribution?

A

Protein binding

71
Q

What is an example of high protein binding?

A

Ibuprofen - 99.98%

Given in a high dose - usually 400mg

72
Q

What is the consequence of high protein binding drugs?

A

You have to give a larger dose

Change the function of the disease as well

73
Q

Define bioavailability

A

Describes the rare and extent (amount) of a drug reaching the systemic circulation and varies from 0 (no drug absorption) to 1 (complete drug absorption)

74
Q

Define clearance

A

The measurement of the ability of the body to eliminate a drug, one do the most important pharmacokinetic parameters

75
Q

Define volume of distribution

A

The hypothetical volume of body fluid that would be required to dissolve the total amount of drug at the same concentration as found in the blood

Effectively a dilution factor representing the extent of drug distribution

76
Q

Terminal half life

A

Time taken for a drug concentration to fall by one-half of its original value, used to describe elimination

77
Q

Amount absorbed

A

Availability x dose

78
Q

Amount of drug in body

A

Volume of distribution x concentration of drug in plasma

79
Q

Concentration of unbound drug in plasma

A

Fraction unbound x concentration of drug in plasma

80
Q

Rate of elimination

A

Clearance x concentration of drug in plasma

81
Q

Rate of elimination

A

Elimination rate constant x amount of drug in body

82
Q

Rate of renal excretion

A

Renal clearance x concentration of drug in plasma

83
Q

Rate of renal excretion

A

Fraction excreted unchanged x rate of elimination

84
Q

What is the whole purpose of drug metabolism?

A

Make the drug more soluble so it can be eliminated in the urine

85
Q

Biliary elimination

A

Can come down in the bike and goes eliminated in the faeces

86
Q

Conjugation

A

CYP450 will put a hydroxyl group on it

87
Q

What is drug metabolism pathway?

A
  1. Phase I - functionalization

2. Phase II - conjugation

88
Q

What are examples of phase I - Functionalization

A
  1. Hydrolysis reactions
  2. Oxidation
  3. reduction
89
Q

CNS target

A

You want a certain amount of lipophilicity and certain amount of greasiness

90
Q

What is an example of CYP450?

A

Avocado

91
Q

What are 4 basic P450 enzymes ?

A
  1. CYP2D6
  2. CYP2C19
  3. CYP2C9
  4. CYP3A4
92
Q

What is CYP3A4?

A

Non-specific
Metabolises a lot of antibiotics
Very variable across the spectrum

93
Q

What is CYP2D6?

A

Polymorphic

94
Q

Cytochrome P450 enzymes

A

Super family of proteins containing harm as a cofactor

terminal oxidase enzyme in electron transfer chains

Over 50,000 distinct P450 proteins identified

95
Q

What is mediated by P450?

A

60% of all human drug metabolism

96
Q

What are drug transporters?

A

Specific transporters that shuttle compounds around the body

Not all about passive permeability

97
Q

What are examples of drug transporters?

A
  1. P-glycoproteins

2. B-sep (bile salt exclusion protein)

98
Q

What is the most important PK parameter?

A

Screening
Gate-keeper to a lot of PK parameter
Done In-vitro -> use battery of systems

99
Q

Why screen for hepatic clearance?

A
  1. High throughout
  2. Readily obtain human data
    - microsomes, S9, hepatocytes, bactosomes
  3. Better define “mechanistic” pharmacokinetics
100
Q

Intrinsic clearance

A

CLi = k.Vd

101
Q

What are the In-vitro approaches?

A
  1. Intrinsic clearance screens
    - measure innate metabolic stability
    - ml/min/g liver
    - tank order
  2. Correction with Fub
    - fraction unbound in blood
    - CLi * Fub
    - corrected rank order
  3. Scale up and apply model of hepatic function
    - prediction of in vivo clearance
    - correlate with known in vivo data
102
Q

What are the optimal physio chemical properties which are essential for good permeation?

A
  1. Size
  2. Polarity - pKa
  3. Hydrogen bonding capacity
  4. PSA
  5. Ionised groups
  6. Lipophilicity
  7. Solubility
103
Q

What is Lipinski rule of 5

A

Optimal oral permeation achieved when:

  1. No more than 5 H-bond donors
  2. No more than 10 H-bind acceptors
  3. Molecular weight < 500da
  4. LogP < 5
104
Q

What are the physio chemical properties

A
  1. Solubility

2. Lipophilicity

105
Q

Solubility

A
  1. Druggist be in solution to get across membrane
  2. Insoluble drugs
    - dissolution rate limiting absorption
    - poor pk profile - may not even work
106
Q

Lipophilicity

A
  1. Can be measured
    - Octanol/water partitioning Coefficients
    - logP = [octanol]/[water]
  • can be calculated
  • Hansch, Moriguchi alogrithm
107
Q

Polar drugs

A

Rapid excretion

108
Q

Lipophilic drugs

A

Rapid metabolism

109
Q

What can clearance of compounds be?

A
  1. Renal
  2. Metabolic
  3. Transport mediated
110
Q

What does metabolism convert?

A

Molecules capable of crossing biological membrane into molecules voided in the ruins

111
Q

What is the major factor in determining clearance route?

A

Lipophilicity

112
Q

Compounds with log D7.4 below 0

A

Significant renal clearance values due to low reabsorption across tubules

113
Q

Compounds above log D7.4 of 0

A

Undergo metabolism

DDD x (17 decks)

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