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ESA 5 - Pharmacology > Pharmacokinetics Concepts > Flashcards

Pharmacokinetics Concepts Flashcards

1
Q

What is pharmacokinetics?

A

The study of movement of a drug into and out of the body - the study of what the body does to the drug

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2
Q

What is pharmacodynamics?

A

The study of drug effect and the mechanisms of action - what the drug does to the body

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3
Q

What is pharmacogenetics?

A

The effect of genetic variability on the pharmacokinetics, or the dynamics of a drug on an individual

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4
Q

What are the main processes involved in drug therapy?

A
  • Pharmaceutical process
  • Pharmacokinetic process
  • Pharmacodynamic process
  • Therapeutic process
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5
Q

What question is asked when considering the pharmaceutical process?

A

Is the drug getting into the patient

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6
Q

What question is asked when considering the pharmacokinetic process?

A

Is the drug getting to its site of action

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7
Q

What aspects does the pharmacokinetic process consist of?

A
  • Absorption
  • Distribution
  • Metabolism
  • Elimination
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8
Q

What question is being asked when considering the pharmacodynamic process?

A

Is the drug producing the required pharmacological effect?

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9
Q

What question is being asked when considering the therapeutic process?

A

Is the pharmacological effect being translated into a therapeutic effect?

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10
Q

Draw a diagram illustrating the relationship between pharmaceutical process, pharmacokinetic process, pharmacodynamic process, and therapeutic process

A
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11
Q

Draw a diagram illustrating the stages of ADME in relation to a time-concentration graph

A
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12
Q

What is meant by oral bioavailability?

A

The fraction of a dose which finds its way into a body compartment, usually the circulation

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13
Q

What is the bioavailability for an intravenous bolus?

A

100%

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14
Q

How is the bioavailability worked out for all other routes apart from IV?

A

You compare the amount reaching the body compartment by that route with intravenous bioavailability

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15
Q

Give the equation for the calculation of oral bioavailability?

A

= area under the curve (oral) / area under the curve (IV)

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16
Q

What is meant by area under the curve when calculating oral bioavailability?

A

The area under the curve of plasma concentration x time post dose - this is the total drug exposure

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17
Q

What factors affect bioavailability?

A
  • Drug formulation
  • Age
  • Food
  • Vomiting/malabsorption
  • Fire pass metabolism
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18
Q

What is first pass metabolism?

A

Any metabolism occuring before the drug enters the systemic circulation

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19
Q

In what locations can first pass metabolism occur?

A
  • Gut lumen
  • Gut wall
  • Liver
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20
Q

What produces the first pass metabolism effect in the gut lumen?

A
  • Gastric acid
  • Proteolytic enzymes
  • Grapefruit juice
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21
Q

What drugs are affected by the first pass metabolism in the gut lumen?

A
  • Benzylpenicillin
  • Insulin
  • Ciclosporin
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22
Q

What produces the first pass affect in the gut wall?

A

P-glycoprotein efflux, which pumps drugs out of the intestinal entrocytes and back into the lumen

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23
Q

What drugs are affected by first pass metabolism in the gut wall?

A

Ciclosporin

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24
Q

What produces the first pass effect in the liver?

A

Drugs get oxidised and conjugated

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25
Q

What drugs are affected by the first pass effect in the liver?

A
  • Propanolol
  • Morphine
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26
Q

What does the distribution of a drug refer to?

A

Its ability to ‘dissolve’ in the body

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27
Q

What are the two key factors associated with drug distribution?

A
  • Protein binding
  • Volume of distribution
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28
Q

When are many drugs bound to circulating proteins?

A

Once they are in the systemic circulation

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29
Q

Give 4 proteins that bind drugs in the systemic circulation?

A
  • Albumin
  • Globulins
  • Lipoproteins
  • Acid glycoproteins
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30
Q

What kind of drugs does albumin bind?

A

Acidic drugs

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31
Q

What kind of drugs do globulins bind?

A

Hormones

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32
Q

What kind of drugs to lipoproteins bind?

A

Basic drugs

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33
Q

What kind of drugs do acid glycoproteins bind?

A

Basic drugs

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34
Q

What binding state must drugs be in to have a pharmacological effect?

A

Most must be unbound (free)

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35
Q

Why must most drugs be unbound in order to have a pharmacological effect?

A

Because only the fraction of the drug that is not protein-bound can bind to the cellular receptors, pass across tissue membranes, gain acess to cellular enzymes etc

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36
Q

What does the level of free drug determine?

A

The action of the drug at its target receptor, and its elimination

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37
Q

What can displacement of drugs from binding sites produce?

A

Protein binding drug interactions

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38
Q

What affect may changes in protein binding have?

A

Can cause changes in drug distributino

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39
Q

When are changes in protein binding important?

A

If one of three criteria are met;

  • High protein binding
  • Low Vd
  • Narrow therapeutic ratio
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40
Q

What factors affect protein binding?

A
  • Hypoalbuminaemia
  • Pregnancy
  • Renal failure
  • Displacement by other drugs
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41
Q

Regarding distribution, what is true of drug that is not bound to plasma proteins?

A

It is available for distribution to the tissues of the body

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42
Q

Are drugs found in body fluids, or in tissues?

A

Some are distributed only to body fluids, whereas others are found extensively in body tissues

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43
Q

What is volume of distribution?

A

A measure of how widely a drug is distributed in body tissues

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44
Q

Give the equation for calculating volume of distribution?

A

= dose / [drug]10

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45
Q

Where is volume of distribution a useful measure?

A

Useful in understanding dosing regimes

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46
Q

What is half life proportional to?

A

Vd and clearance

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47
Q

What is the body fluid distribution in a 70kg man?

A
  • Intracellular space 55% (23L)
  • Intravascular space 12% (5L)
  • Interstitial space 33% (14L)
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48
Q

What can tissue distribution be affected by?

A
  • Specific receptor sites in tissues
  • Regional blood flow
  • Lipid solubility
  • Active transport
  • Disease states
  • Drug interactions
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49
Q

What is a drug initially metabolised by?

A

Phase 1 enzymes

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50
Q

What happens once a drug has been metabolised by phase 1 enzymes?

A

CYPs perform a variety of functions

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51
Q

What functions are performed by CYPs?

A
  • Oxidation
  • Dealkylation
  • Reduction
  • Hydrolysis
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52
Q

What happens after CYPs have performed their functions on drugs?

A

It either;

  • Gets metabolised by phase II enzymes
  • Go to the kidney
  • Go to the gallbladder
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53
Q

What happens to drugs metabolised by phase II enzymes?

A

They then get conjugated with;

  • Glucoronide
  • Sulphate
  • Glutathione
  • N-acetyl
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54
Q

What happens to the products of conjugation of drugs that have gone down the phase II metabolism path?

A

They go to the gallbladder or the kidney

55
Q

What does whether the products of phase II metabolism go to the kidney or the gallbladder depend on?

A

The molecular weight

56
Q

What is true of the end product of conjugation of phase II metabolised drugs?

A

They are water soluble

57
Q

What is the advantage of the products of conjugation of phase II metabolised drugs being water soluble?

A
  • It enables rapid elimination from the body
  • They are usually pharmacologically inactive
58
Q

When do drugs go the kidney after phase I metabolism?

A

If the molecular weight is <300

59
Q

What happens to the drugs that go to the kidney?

A

They are excreted in urine

60
Q

When do drugs go the gallbladder after phase I metabolism?

A

If the molecular weight is >300

61
Q

What happens to the drugs that go to the gallbladder?

A

They are excreted in bile

62
Q

When can an active metabolite be produced?

A
  • When a pharmacologically inactive compound is metabolised to one with pharmacological activity
  • When a pharmacologically active compound is metabolised to other active compounds
63
Q

What is it called when a drug is metabolised to a pharmacologically active compound in the body?

A

A ‘pro-drug’

64
Q

Give two examples of pro-drugs

A
  • Inactive enalaprilat to active enalapril
  • L-dopa metabolised to more active metabolite
65
Q

What is the advantage of L-dopa being metabolised to a more active metabolite?

A

Improves distribution, and allows it to cross the blood brain barrier

66
Q

Give two examples of where pharmacologically active compounds are metabolised to other active compounds

A
  • Codeine to morphine
  • Lorsartan to EXP3174
67
Q

What are oxidation and reduction in phase 1 of drug metabolism in part dependant on?

A

Cytochrome P450 family of enzymse

68
Q

What can the activity of cytochrome P450 enzymes be influenced by?

A

Enzyme-inducing and enzyme-inhibiting drugs

69
Q

Other than enzyme-inducing and -inhibiting drugs, what else affects cytochrome P450 enzymes?

A
  • Age
  • Liver disease
  • Hepatic blood flow
  • Cigarette and alcohol consumption
70
Q

Other than acting on cytochrome P450 drugs, what else do enzyme inhibiting and inducing drugs do?

A

Alter the rate of metabolism of other drugs

71
Q

Where are the cytochrome P450 enzymes present?

A

Mainly in the liver, but also in the gut and lungs

72
Q

What are the most important cytochrome P450 types?

A
  • 2D6
  • 2C9
  • 2C19
  • 3A
73
Q

How does CYP2D6 vary depending on race?

A
  • Absent in 7% of Caucasians
  • Hyperactive in 30% in East Africans
74
Q

What does CYP2D6 metabolise?

A
  • Codeine
  • Beta-blockers
  • Tricyclics
75
Q

What is CYP2D6 inhibited by?

A
  • Fluxoetine
  • Paroxetine
  • Haloperidol
  • Quinidine
76
Q

How does CYP2C9 vary depending on race?

A

Absent in 1% of Caucasian and Blacks

77
Q

What does CYP2C9 metabolise?

A
  • Most NSAIDs
  • S-warfarin
  • Phenytoin
  • Tolbutamide
78
Q

What is CYP2C0 inhibited by?

A

Fluconazole

79
Q

What is CYP2CP induced by?

A
  • Carbamazepine
  • Ethanol
80
Q

How does CYP2C19 vary depending on race?

A
  • Absent in 30% of Asians
  • Absent in 5% of Caucasians
81
Q

What does CYP2C19 metabolise?

A
  • Diazepine
  • Phenytoin
  • Omeprazole
82
Q

What is CYP2C19 inhibited by?

A
  • Ketoconazole
  • Omeprazole
  • Isoniazid
  • Fluoxetine
  • Ritonavir
83
Q

What is CYP2C19 induced by?

A

Rifampicin

84
Q

What is CYP3A involved in the metabolism of?

A
  • Calcium channel blockers
  • Benzodiazepines
  • HIV protease inhibitors
  • Most statins
  • Cyclosporin
  • Non-sedating anti-histamines
85
Q

What drugs act as CYP3A inhibitors?

A
  • Anti-fungals
  • Cimetidine
  • Macrolides
  • Grapefruit juice
86
Q

Give 3 anti-fungals that act as CYP3A inhibitors

A
  • Ketoconazole
  • Flucoanzole
  • Itraconazole
87
Q

What drugs act as CYP3A inducers?

A
  • Carbamazepine
  • Phenytoin
  • Rifampicin
  • Ritonavir
  • St Johns Wort
88
Q

What are cytochrome P450 enzymes?

A

A superfamily of isoforms

89
Q

What % of human drug metabolism are cytochrome P450 enzymes responsible for?

A

Around 90%

90
Q

Give two examples of toxins metabolised by cytochrome P450 enzymes

A
  • Carcinogens
  • Pesticides
91
Q

What is the result of the genetic differences in cytochrome P450 enzymes?

A

There are genetic differences in metabolism

92
Q

Clinically, where is metabolism important?

A

In drug prescribing

93
Q

What should be considered while prescribing to prevent interactions?

A

Over the counter medications and food

94
Q

What factors are important in the metabolism of drugs?

A
  • Race
  • Age
  • Sex
  • Species
  • Clinical or physiological condition
95
Q

Where is the consideration of the effect of race on drug metabolism important?

A

In the development of pharmacogenetics

96
Q

How does age affect the metabolism of drugs?

A

It is reduced in children and the elderly

97
Q

Give an example of where metabolism is affected by gender?

A

Women are slower ethanol metabolisers

98
Q

When is the consideration of the effect of species on drug metabolism important?

A

When considering drug development

99
Q

What is the main route of drug elimination?

A

The kidney

100
Q

Other than the kidneys, what are the other routes of drug metabolism?

A
  • Lungs
  • Breast milk
  • Sweat
  • Tears
  • Genital secretions
  • Bile
  • Saliva
101
Q

What processes determine the renal excretion of drugs?

A
  • Glomerular filtration
  • Passive tubular reabsorption
  • Active tubular secretion
102
Q

What drugs have their excretion affected by glomerular filtration?

A

Unbound drugs, e.g. gentamicin

103
Q

Give an example of a drug where the excretion is affected by passive tubular reabsorption?

A

Aspirin

104
Q

What is passive tubular reabsorption affected by?

A
  • Urine flow rate
  • pH
105
Q

Give an example of a drug where the excretion is affected by active tubular secretion

A

Penicillin

106
Q

What is clearance?

A

The ability of the body to excrete the drug

107
Q

What is clearance mostly affected by?

A

GFR - if the GFR is reduced, the clearance is reduced

108
Q

How is half life related to clearance?

A

They are inversely proportional

109
Q

What are the categories of elimination kinetics?

A
  • First order kinetics
  • Zero order kinetics
110
Q

Describe the elimination in first order kinetics

A

Linear

111
Q

What is meant by elimination being linear?

A

The rate of elimination is proportional to the drug level - a constant fraction of drug is eliminated in unit time

112
Q

Can half life be defined with first order kinetics?

A

Yes

113
Q

Describe the elimination of drug in zero-order kinetics

A

Non-linear

114
Q

What is meant by non-linear elimination?

A

The rate of elimination is constant

115
Q

What kind of kinetics do most drugs exhibit at high doses?

A

Zero order

116
Q

Why do most drugs exhibit zero order kinetics at high doses?

A

Because the receptors/enzymes become saturated

117
Q

What is the problem with zero order drugs?

A

They are more likely to result in toxicity

118
Q

Why are zero order drugs more likely to result in toxicity?

A
  • No half life is calculable
  • Small dose changes may produce large increments in dose, or lead to toxicity
119
Q

What are the potential reasons for drugs requiring monitoring?

A
  • Phamacokinetic reasons
  • Known toxic effects
120
Q

What are the pharmacokinetic reasons for drug monitoring?

A
  • Zero order kinetics
  • Long half-life
  • Narrow therapeutic window
  • At greater risk of drug-drug interactions
121
Q

Give two examples of known toxic effects of drugs that would necessitate drug monitoring

A
  • Bone marrow suppression
  • Alteration in U&Es
122
Q

How long does it take to reach a steady state during repeated drug administration?

A

3-5 half lives, generally irrespective of dose or frequency of administration

123
Q

How long does it take to eliminate most of the drug once a steady state is reached?

A

4-5 half lives

124
Q

What is the equation for calculating loading doses?

A

Vd x [Drug]target

125
Q

What is the equation for calculating half life?

A

loge0.5 / k

= 0.693 / k

126
Q

What is k?

A

The elimination rate constant, which is determined from the slope of the curve

127
Q

What determines k?

A

The ratio of clearance to volume of distribution

128
Q

How do you calculate half life from volume of distribution?

A

Vd / Cl

129
Q

What is the result of half life being equal to Vd / Cl?

A

Half life is proportional to volume of distribution, or inversely proportional to clearance

130
Q

What might you have to take account of when calculating half life?

A

Chronic kidney disease

131
Q

Why may you have to account for chronic kidney disease in the half life calculation?

A

Clearance from the kidney is proportional to renal function (GFR), and so half life is inversely proportional to clearance

132
Q

What is the result of most drugs not remaining in the plasma?

A

Distribution occurs in 2 or more compartments

133
Q

Is the equilibrium of drugs between different body compartments equal?

A

No

134
Q

What is the result of the equilibrium of drugs between different compartments being different?

A

The rate of elimination can be different

ESA 5 - Pharmacology (28 decks)

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