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Pharmacology > Basic Principles of ADME > Flashcards

Basic Principles of ADME Flashcards

1
Q

What does ADME stand for?

A

Absorption
Distribution
Metabolism
Elimination

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2
Q

What does a drug PK give us?

A

Which dose to give
Which administration route
How often to give a dose
Which administration formulation

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3
Q

How do we get drug PK data?

A

Through experiments done as part of development research

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4
Q

What are the stages in drug making?

A

Drug discovery
Preclinical experiments
Clinical trials
Phase IV

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5
Q

What happens in drug discovery?

A

Identify target

New drug synthesis

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6
Q

What happens in preclinical experiments?

A

In vitro + vivo
Testing drug activity
1st PK + PD data

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7
Q

What happens in clinical trials?

A

Phase I = safety + dose range
Phase II = safety, efficacy, dose range + target disease population
Phase III = efficacy + comparison

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8
Q

What happens in phase IV?

A

Observation = 10-15 years

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9
Q

What is drug absorption?

A

Mass transfer process that involves the movement of unchanged drug molecules from site of administration into blood stream

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10
Q

What is active transport?

A

Uniport, antiport + symport

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11
Q

What is passive diffusion?

A

No involvement of membrane, slowest step, larger molecules diffuse more slowly

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12
Q

What is facilitated diffusion?

A

Channel protein + carrier protein, sugar, amino acid + drugs with similar structures pass

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13
Q

What is the cell membrane NOT permeable to?

A

High polarity
High molecular weight
Conformational freedom

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14
Q

Describe uniport

A

Mediate transport of single drug
Facilitate mode of diffusion
Transport of non-diffusible substances
Never in contact with hydrophobic core

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15
Q

Describe antiport

A

Coupled movement against conc gradient

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16
Q

Describe symport

A

Transport 2 different substances simultaneously

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17
Q

What is an example of uniport?

A

GLUT1 glucose carrier

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18
Q

What is an example of antiport?

A

3 Na+/ Ca2+ antiporter in cardiac muscles

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19
Q

What is an example of symport?

A

2 Na+/ glucose symporter

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20
Q

What are the parameters that influence absorption?

A

Physiochemical properties of drug
Pharmaceutical dosage form
Anatomical + physiological characteristics
Administration route

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21
Q

What are examples of physiochemical properties of drug?

A

Size
Hydrophilic
Lipophilic

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22
Q

What are examples of pharmaceutical dosage form?

A

Sustained dosage form

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23
Q

What are examples of administration route?

A

Systemic or topical

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24
Q

What is dose?

A

Specific measured amount of drug needed to achieve a specific plasma conc

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25
Q

What is plasma conc?

A

Amount of drug which reaches the blood stream , gets distributed in body + so achieves specific conc

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26
Q

What happens if specific conc reaches target site?

A

= pharmacological effect

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27
Q

What is exposure?

A

Plasma conc vs time

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28
Q

What is area of curve equal to?

A

Actual body exposure to drug after administration of dose

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29
Q

How do you calculate area under the curve?

A 
          Clearance
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30
Q

How do you calculate AUC for IV?

A

Extrapolated plasma conc/ elimination rate constant

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31
Q

What is bioavailability?

A

Amount of drug reaching circulatory system from delivery system used

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32
Q

What does oral bioavailability depend on?

A

Absorption rate

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33
Q

Why is intravenous 100% bioavailability?

A

Administrated straight into circulation

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34
Q

What is the bioavailability factor?

A

Ratio of AUC of orally or intravenous administrated drug

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35
Q

What is the equation for bioavailability factor (F)?

A

AUC oral
————- X 100
AUC iv

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36
Q

What factors influence bioavailability?

A

Lipid solubility + chemical form of drug = salt factor
Formulation = bioequivalence
Co-administration of other drugs
Presence of comorbidity affecting absorbance site
Susceptibility to gastric acid + enzymes
First-Pass effect

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37
Q

What are examples of comorbidity affecting absorbance site?

A

Diarrhoea

Vomiting

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38
Q

What happens when a drug is not-H2O soluble?

A

Low bioavailability

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39
Q

How do you increase solubility of non-H2O soluble drugs?

A

Formulated as salts

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40
Q

What is bioequivalence?

A

Ensures all drug formulation on market has same bioavailability

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41
Q

What is drug distribution?

A

Reversible mass transfer of drug from one location to another within the body

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42
Q

What happens once the drug is absorbed?

A

Conc gradient exists

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43
Q

What does drug distribution depend on?

A

Blood flow

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44
Q

What happens if a drug is more lipid soluble?

A

More chance of reaching target

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45
Q

What must drugs do to interact with target?

A

Pass through capillary walls into intestinal fluid

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46
Q

Are drugs distributed equally across all organs?

A

NO

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47
Q

How does blood flow influence drug distribution?

A

Intensity of it

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48
Q

How does exercise increase drug distribution?

A

Cardiac output increases 5-6x

= perfusion increases = distribution increases

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49
Q

How does concomitant diseases decrease drug distribution?

A

Heart failure = not enough perfusion
= distribution takes longer
= peak response to dose delayed

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50
Q

How does decreased renal clearance decrease drug distribution?

A

Delay drug excretion

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51
Q

What else can decrease/increase drug distribution?

A

Shock

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52
Q

What may drugs be held by plasma compartments by?

A

Albumin
Lipoproteins
α1- acid glycoproteins

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53
Q

Describe albumin protein binding

A

Weak acids bind

Have 2 binding sites

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54
Q

Describe α1- acid glycoproteins binding

A

Cationic drugs at physiological pH

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55
Q

When is binding reversible?

A

Therapeutic conc

56
Q

What must the drug be to enter target?

A

Unbound = free to leave plasma + diffuse + enter target

57
Q

How do you calculate fraction of unbound drug (%)?

A

Total drug conc

58
Q

What does it mean if FU is <5-10%?

A

Highly plasma protein bound drugs

59
Q

What happens when you increase free unbound drug?

A

Decrease in plasma protein synthesis

60
Q

How do you calculate vol of distribution?

A

Drug serum conc (mg/L)

61
Q

What is vol of distribution?

A

Vol of fluid required to contain total dose of drug in the body in same conc as that present in plasma

62
Q

What does vol of distribution vary with?

A

Body weight

63
Q

How many PK compartment models are there?

64
Q

What is the first PK compartment model?

A

Organs + tissues with high blood flow

= heart, kidney, liver, lungs + brain

65
Q

What is the second PK compartment model?

A

Organs + tissues with low blood flow

= bone, bladder + peritoneal cavity

66
Q

What happens in first PK compartment model?

A

Drug absorbed then immediately distributed

67
Q

What is the second PK compartment model divided into?

A

Central + peripheral

68
Q

What is the central compartment?

69
Q

What is the peripheral compartment?

A

Tissues where distribution of drug is slower

70
Q

What is the prime site of drug metabolism?

71
Q

What is the ultimate elimination organ?

72
Q

Which organ is responsible for 1st-pass effect?

73
Q

Where are most drugs metabolised?

74
Q

What enzymes is involved in liver metabolism?

A

Cytochromes P450

75
Q

Where are cytochrome P450s enzymes located?

A

Hepatocytes of liver

76
Q

What is hepatic clearance of drugs?

A

Complex multistep process looking to removal of drugs from circulation

77
Q

What is hepatic clearance (CLH)

A

Vol of blood from which drug is completely removed by liver per unit time

78
Q

How do you calculate CLH?

A

Hepatic blood flow (QH) X hepatic extraction ratio (EH)

79
Q

What is hepatic elimination ration (EH)

A

Fraction of drug extracted from blood during single pass through liver

80
Q

What factors is hepatic clearance dependent on?

A

Fraction of unbound drug to albumin
Liver blood flow
Liver intrinsic clearance

81
Q

What happens if parent compound is lipophilic?

A

Metabolite hydrophilic

82
Q

What happens to H2O-soluble drugs?

A

Easily excreted in urine

83
Q

What happens to drugs administrated IV, ID or SD?

A

Enter systemic circulation directly = reach target organs before hepatic modification

84
Q

What happens to oral drugs?

A

Absorbed in GI tract + delivered by portal vein to liver

85
Q

What is 1st-pass effect?

A

Allow liver to metabolise drugs before systemic circulation

86
Q

What do oral drugs with extensive 1st-pass metabolism need?

A

Administration at a larger dose than IV formulation

87
Q

What do drugs with low 1st-pass effect need?

A

Similar or slightly higher dose than IV

88
Q

What does it mean if drugs have NO 1st-pass effect?

A

Low bioavailability

89
Q

Do sublingual + rectal avoid 1st-pass effect?

90
Q

What are consequences of drug metabolism?

A

Metabolite products are less pharmacologically active

91
Q

What the exceptions to consequences of drug metabolism?

A

Metabolite more active = pro-drugs
Metabolite is toxic
Metabolite is carcinogenic

92
Q

What is small intestine metabolism important for?

A

Orally ingested chemicals

93
Q

What type of reactions occur in drug metabolism?

A

Phase I
Phase II
Phase III

94
Q

Describe Phase I reaction in drug metabolism

A

Convert parent compound into chemically active more polar metabolite
By adding/ unmasking functional groups

95
Q

Describe Phase II reaction in drug metabolism

A

Occur at chemically reactive sites
Conjugation wit endogenous substrate to further increase aq solubility
Metabolites inactive

96
Q

Describe Phase III reaction in drug metabolism

A

Transmembrane transport
Efflux of metabolites + parent compound to bile + urine
Antiporter activity

97
Q

Describe oxidation reactions by Cytochrome P450s

A

Cytochrome P450s
O2 incorporated into drug
Oxidation = loss of part of drug

98
Q

Describe Cytochrome P450s

A

Haem-containing proteins with smooth ER
12 gene families expressed in humans
GYP P450 nomenclature is genetically based

99
Q

What factors affect metabolism?

A

Physio-chemical factors
Biological factors
Environmental factors

100
Q

What are examples of biological factors?

A

Age, gender, genetics + state of health

101
Q

What are examples of environmental factors?

A

Diet, stress, season (time of day) + pharmacokinetic drug-drug interactions

102
Q

What is an example of Phase I reaction?

103
Q

What is elimination?

A

Any process involved in excretion of drugs from the body

104
Q

What are the major routes of elimination?

A 
Kidney = urine
Liver = bile (faeces)
105
Q

What are the minor routes of elimination?

A

Exhalation, sweat, saliva + breast mile

106
Q

What happens in renal drug elimination?

A

Filtration in glomerulus
Reabsorption
Tubule excretion

107
Q

What happens in filtration in renal drug elimination?

A

Free or unbound drugs filtered

No albumin can pass through

108
Q

What happens in reabsorption in renal drug elimination?

A

Glucose + amino acids reabsorbed

No hydrophilic drugs reabsorbed BUT lipophilic do

109
Q

What happens if metabolism increases H2O-solubilty?

A

Prevent reabsorption

110
Q

What happens if change in pH/charge?

A

Prevent reabsorption

111
Q

What is renal clearance?

A

Vol of plasma per unit time that get filtered of a drug

112
Q

What does renal clearance give no information about?

A

How much drug cleared

113
Q

What gives info about the drug being cleared?

A

Rate of elimination

114
Q

How do you calculate rate of elimination?

A

Renal clearance X drug plasma conc

115
Q

What are most drugs cleared by?

A

1st order kinetics

116
Q

What is the half-life for each drug?

A

Individual + constant

117
Q

What are closely related to renal clearance?

A

Glomerular filtration rate

Creatinine clearance

118
Q

What is glomerular filtration rate (GFR)?

A

Flow rate of a drug that is being filtered in Bowman’s capsule

119
Q

What is ROE?

A

Amount of drug eliminated

120
Q

What is ROE dependent on?

A

Renal clearance + drug plasma conc

121
Q

Why is rate of metabolism proportional to drug plasma conc?

A

Because metabolic enzymes are mot saturated

122
Q

What happens if there is a higher drug plasma conc?

A

Higher the elimination rate

123
Q

Is the same amount of drug metabolised the same amount getting eliminated?

124
Q

What is half-life?

A

Time it takes to eliminate 50% of drug

125
Q

What does half-life determine?

A

Dose + dosing interval

126
Q

What is the equ for t1/2?

127
Q

What % of drug is always excreted after 5 half-life times?

128
Q

Which part of the graph is zero order kinetics?

129
Q

What is the amount of drug metabolised per unit time in zero order kinetics?

130
Q

When does zero order kinetics mostly happen + why?

A

Through overdoses = drug accumulates in body = increased side effects

131
Q

What is biliary excretion?

A

Active secretion of endogenous + exogenous drugs/substances from hepatocytes in bile + duodenum

132
Q

What is multiple dosing?

A

Some drugs given more than once via multiple doses = to achieve constant drug plasma levels

133
Q

What is steady state?

A

Situation in which in take of drug is in eqm with elimination

134
Q

When is steady state reached?

A

After 5 half life

135
Q

What does multiple dosing depend on?

Pharmacology (40 decks)

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