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Drugs and Therapy Flashcards

1
Q

Define

Glomerular filtration

A

the first step in making urine. It is the process that your kidneys use to filter excess fluid and waste products out of the blood into the urine collecting tubules of the kidney, so they may be eliminated from your body

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2
Q

What are testing in the four phases of clinical development?

A

Phase I - Inital safety/tolerability

Phase II - Initial efficacy/proof-of-concept/dose-response

Phase III - Large scale trials efficacy/benefit

Phase IV - Postmarketing surveillance

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3
Q

In order to achieve a steady state, maintenance dose rate (DR) must equal what?

A

RE

i.e. DR = CL x target Cp

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4
Q

Definition

one in which neither the participants nor the experimenters know who is receiving a particular treatment

A

Double-blind

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5
Q

Define

Potency

A

a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity

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6
Q

A drug with a large therapeutic window is said to be ______ than a drug with a small therapeutic window

A

A drug with a large therapeutic window is said to be safer than a drug with a small therapeutic window

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7
Q

What are p-glycoproteins involved in?

A

Uptake and efflux of a range of drugs

  • Influence plasma and tissue [drug]
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8
Q

What are the advantages of fast-tracking a clinical trial?

A
  • Cheaper
  • Demand (urgent disease)
  • Hope
  • Crisis resolution
  • Cancer (no alternative treatment)
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9
Q

What is structure based drug designed?

A

Using the structure of the receptor target itself to deduce the chemical structure that would interact with the receptor

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10
Q

Is seizures induced by electrical stimulation an example of acute or chronic animal model?

A

Acute

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11
Q

Define

Teratogenic effects

A

an agent that can disturb the development of the embryo or fetus

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12
Q

Define

Volume of distribution (Vd)

A

the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood plasma

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13
Q

Definition

the development of adverse effects as the result of long term exposure to a toxicant or other stressor

A

Chronic toxicity

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14
Q

Definition

an inert substance or treatment which is designed to have no therapeutic value

A

Placebo

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15
Q

Definition

the highest dose of a medicine or treatment that will produce the desired effect without resulting in unacceptable side effects

A

Maximum tolerated dose (MTD)

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16
Q

What does drug metabolism do and what does it depend on?

A
  • Makes lipid soluble drugs more water soluble so that they can be excreted via the kidneys
  • Depends on many different types of enzymes
    • Mostly located intracellularly
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17
Q

True or False:

Phase II drug metabolism is not considered important for drug-drug interactions

A

True

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18
Q

What does the degree of plasma protein binding depend on?

A
  • [free drug]
  • affinity of drug for binding sites
  • [plasma protein]
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19
Q

Definition

a substance which interferes with or inhibits the physiological action of another

A

Antagonist

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20
Q

Illustrate the Ames test

A
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21
Q

Define

Chronic toxicity

A

the development of adverse effects as the result of long term exposure to a toxicant or other stressor

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22
Q

Define

Antagonist

A

a substance which interferes with or inhibits the physiological action of another

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23
Q

What are the three main categories of drug toxicity that need to be explored?

A

Systemic toxicity

Carcinogenic effects

Teratogenic effects

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24
Q

Definition

a drug that has shown affinity for a specific molecular target

A

Hit candidate

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25
Q

Definition

a compound (small molecule, antibody, etc.) with strong therapeutic potential and whose activity and specificity have been optimised

A

Candidate drug

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26
Q

True or False:

It is important to conduct animal studies in all stages of lead discovery and optimisation

A

True

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27
Q

Definition

the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood plasma

A

Volume of distribution (Vd)

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28
Q

Definition

an agent that can disturb the development of the embryo or fetus

A

Teratogenic effects

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29
Q

Definition

substances which alter the catalytic action of the enzyme and consequently slow down, or in some cases, stop catalysis

A

Enzyme inhibition

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30
Q

Definition

Highest dose at which there was not an observed toxic or adverse effect

A

No (observed) adverse effect level (NOAEL)

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31
Q

Define

High-throughput screening (HTS)

A

recent scientific methods relevant to the field of chemistry and biology, in which hundreds of thousands of experimental samples are subjected to simultaneous testing under given conditions

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32
Q

A Vd > 0.55L/kg indicates what?

A

The drug is actively concentrating in certain areas

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33
Q

Filtering a primary hit candidate into validated hit candidates (secondary screen) involved the drug demonstrating what?

A

Confirm affinity/potency/selectivity

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34
Q

What is a hit candidate?

A

A drug that successfully bind the target

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35
Q

Definition

what the body does to the drug

A

Pharmacokinetics

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36
Q

Definition

the degree to which medications attach to proteins within the blood

A

Plasma protein binding (PPB)

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37
Q

What factors affect drug distribution?

A
  • How easily it moves outs of the vaculature
    • movement of drug across cell membranes
    • binding to plasma proteins
  • How well it is ‘delivered’ to tissues
    • blood flow to particular regions
  • How well it binds to tissue components
    • binding to extravacular sites including tissues
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38
Q

Definition

a feedback mechanism resulting from the combined roles of the liver and intestine

A

Enterohepatic recycling

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39
Q

Definition

A term used to describe the situation when both the researcher and the participant in a research study know the treatment the participant is receiving

A

Open-label

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40
Q

Drug Z is a substrate for p-glycoproteins. Predict the effect of inhibiting p-glycoproteins.

A. increased absorption of Drug Z from the GIT

B. decreased movement of Drug Z into the brain

C. increased elimination of Drug Z via the kidneys

A

Drug Z is a substrate for p-glycoproteins. Predict the effect of inhibiting p-glycoproteins.

A. increased absorption of Drug Z from the GIT

B. decreased movement of Drug Z into the brain

C. increased elimination of Drug Z via the kidneys

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41
Q

Definition

the transfer of materials from peritubular capillaries to the renal tubular lumen; it is the opposite process of reabsorption

A

Tubular secretion

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42
Q

Define

Single-blind

A

relating to, or being an experimental procedure in which the experimenters but not the subjects know the makeup of the test and control groups during the actual course of the experiments

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43
Q

What does knowledge of a drugs pharmacokinetics enable?

A
  • Decisions about dosing
    • how much
    • how often
    • by which route
  • Prevention of dose-dependent adverse effects
  • Prediction & avoidance of pharmacokinetic drug interations
  • Prediction of interpatient variability
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44
Q

The average cost of R&D for a new drug is:

a) $50 million
b) $400 million
c) $1 billion
d) $2 billion

A

The average cost of R&D for a new drug is:

a) $50 million
b) $400 million
c) $1 billion

d) $2 billion

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45
Q

Define

Zero order kinetics

A

a way of describing how the body uses and breaks down some medicines. While the rate at which the body eliminates most drugs is proportional to the concentration administered, known as first order kinetics, drugs that work by this mechanism work at a predictable, constant rate

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46
Q

When wouldn’t healthy volunteers be used in a Phase I trial?

A

When a drug has known toxicity (i.e. chemotherapy)

Urgent need/fast-tracking (COVID-19)

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47
Q

What are the main features of a ATP-binding cassette (ABC) transporters?

A
  • Active transporters involved in cell efflux
  • Includes p-glycoproteins
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48
Q

Define

Prodrug

A

a medication or compound that, after administration, is metabolized (i.e., converted within the body) into a pharmacologically active drug

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49
Q

Definition

toxic effects that occur at multiple sites

A

Systemic toxicity

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50
Q

Definition

relating to, or being an experimental procedure in which the experimenters but not the subjects know the makeup of the test and control groups during the actual course of the experiments

A

Single-blind

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51
Q

What is the plasma half-life difference between zero and first order drug elimination?

A

Zero order: Half-life will vary with plasma []

First order: Half-life is constant

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52
Q

Where does Phase I drug metabolism occur?

A

Liver, but also in other tissues

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53
Q

Define

Enzyme inhibition

A

substances which alter the catalytic action of the enzyme and consequently slow down, or in some cases, stop catalysis

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54
Q

Define

Pharmacophores

A

a part of a molecular structure that is responsible for a particular biological or pharmacological interaction that it undergoes

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55
Q

How does analysis of pathophysiology help us find new drug targets?

A

Understanding of pathways involved in disease determines novel target

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56
Q

Define

Placebo

A

an inert substance or treatment which is designed to have no therapeutic value

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57
Q

Definition

an initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down to a lower maintenance dose

A

Loading dose (LD)

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58
Q

How can we validate a drug target?

A

By knocking it out and seeing the result

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59
Q

Filtering a screening library into a primary hit candidate (primary screen) involves the drug demonstrating what?

A

Activity against the target (affinity)

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60
Q

Why is a loading dose sometimes necessary?

A

Some drugs have a very long time to achieve steady state

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61
Q

What does QSAR involve?

A

Using a pharmacophore and relating physical properties of a series of compounds

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62
Q

What is [drug] plasma (Cp) equal to?

A

Cp = dose rate (DR) / Clearance

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63
Q

Definition

a chemical compound that has pharmacological or biological activity likely to be therapeutically useful, but may nevertheless have suboptimal structure that requires modification to fit better to the target

A

Lead compound

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64
Q

What happens if the drug plasma concentration is lower than the therapeutic window?

A

No benefit - unnecessary risk

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65
Q

Predict the difference in renal clearance between:

  • a very lipophilic drug
  • a highly ionised drug
  • a biological (i.e. large molecule)
A

Lipophilic drug - very little renal clearance. High rate of reabsorption

Ionised drug - higher rate of renal clearance

Biological drug - very little renal clearance. Too large to be filtered

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66
Q

How do you calculate volume of distribution (Vd)?

A

Vd = dose / [plasma]

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67
Q

What type of drugs usually warrant a loading dose (LD)?

A

Usually needed for drugs with high volume of distribution

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68
Q

Other than urine and faeces, what are some routes of excretion of drugs?

A

Lungs, sweat, saliva, mucous, tears and breast milk

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69
Q

What are the two types of enzymatic metabolism reactions?

A

Phase I reactions: makes the drug more water-soluble through redox/hydrolysis reactions that increase polarity

Phase II reactions: makes the dug more water-soluble through combining the drug with an endogenous molecule

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70
Q

Definition

a way of describing how the body uses and breaks down some medicines. It is a concentration-dependent process (i.e. the higher the concentration, the faster the clearance)

A

First order kinetics

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71
Q

Define

Phase II enzymatic metabolism

A

m involves reactions that chemically change the drug or phase 1 metabolites into compounds that are soluble enough to be excreted in urine. In these reactions, the molecule (drug or metabolite) is attached to an ionisable grouping

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72
Q

What are the design features of a acute systemic toxicity test? What information can be obtained?

A
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73
Q

Define

Selectivity

A

a drug’s ability to preferentially produce a particular effect and is related to the structural specificity of drug binding to receptors

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74
Q

True or False:

Dosage interval affects the rate that the mean steady state concentration is achieved

A

False

Dosage interval does not affect the rate that the mean steady state concentration is achieved

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75
Q

What occurs when drug interaction results in enzyme induction?

A

Some drugs can increase activity/levels of the enzymes that metabolism them (e.g. alcohol tolerance)

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76
Q

Why does a paracentamol OD cause hepatotoxicity?

A

The conjugates get overwhelmed causing a build up of the toxic NAPQI product

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77
Q

Definition

a rule of thumb to evaluate druglikeness or determine if a chemical compound with a certain pharmacological or biological activity has chemical properties and physical properties that would make it a likely orally active drug in humans

A

Lipinski Rule of 5

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78
Q

Definition

a plasma membrane protein which acts as a localized drug transport mechanism, actively exporting drugs out of the cell

A

P-glycoproteins

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79
Q

How do you calculate a loading dose?

A

LD = Vd x target [plasma]

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80
Q

Definition

a chemical substance found within an organism that is not naturally produced or expected to be present within the organism

A

Xenobiotics

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81
Q

Define

Loading dose (LD)

A

an initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down to a lower maintenance dose

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82
Q

Where do lipophillic drugs tend to distribute to?

A

Cells enriched with fat

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83
Q

What does in vivo profiling reveal?

A
  • Do molecular and cellular effects translate to predicted pharmacological action in intact tissue?
  • Off target effects?
  • Does in vivo potency match with pharmacokinetic properties of compound?
  • Effect of repeated/long-term administration of drug
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84
Q

Definition

a superfamily of enzymes containing heme as a cofactor that function as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compounds, as well as for hormone synthesis and breakdown

A

Cytochrome P450

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85
Q

What are the two main types of transporters involved in carrier mediated transport?

A

Solute carrier transporters

ATP-binding cassette (ABS) transporters

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86
Q

Definition

the process of assigning clinical trial participants to treatment groups such that each participation has a known (usually equal) chance of being assigned to any of the groups

A

Randomisation

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87
Q

What are the design features of a teratogenic effect test? What information can be obtained?

A
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88
Q

True or False:

Protein-bound molecules are not available to extort pharmacological effects

A

True

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89
Q

Definition

a process in which a molecule (e.g. a drug) induces (i.e. initiates or enhances) the expression of an enzyme

A

Enzyme induction

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90
Q

What occurs when drug interaction results in enzyme inhibition?

A

The drugs are metabolised by the same enzyme. If administered together, they will compete for the metabolising enzyme

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91
Q
A
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92
Q

True or False:

Phase I drug metabolism is a potential site for drug-drug interactions

A

True

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93
Q

Define

Lead compound

A

a chemical compound that has pharmacological or biological activity likely to be therapeutically useful, but may nevertheless have suboptimal structure that requires modification to fit better to the target

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94
Q

No (observed) adverse effect level (NOAEL)

A

Highest dose at which there was not an observed toxic or adverse effect

95
Q

Define

Double-blind

A

one in which neither the participants nor the experimenters know who is receiving a particular treatment

96
Q

Is surgically-induced hypertension an example of acute or chronic animal model?

A

Chronic

97
Q

Define

Pharmacogenomics

A

the branch of genetics concerned with determining the likely response of an individual to therapeutic drugs.

98
Q

Definition

increase the risk of cancer by altering cellular metabolism or damaging DNA directly in cells, which interferes with biological processes, and induces the uncontrolled, malignant division, ultimately leading to the formation of tumors

A

Carcinogenic effects

99
Q

Where does Phase II drug metabolism usually occur?

A

Liver

100
Q

The elimination of drugs with zero/first order kinetics is independent of [drug] plasma

A

The elimination of drugs with zero order kinetics is independent of [drug] plasma

101
Q

What is the average Total Body Water (TBW) volume of a 70kg man?

A

40L

102
Q

Where do very polar drugs tend to distribute to?

A

Circulation and interstitial fluid

103
Q

What are the design features of a chronic systemic toxicity test? What information can be obtained?

A
104
Q

What type of drugs tend to be confined to the circulation?

A

Very large molecules

105
Q

What does a pharmacophore model define?

A

The structure necessary for drug binding (and activation or blockade)

106
Q

What do cytochrome P450 enzymes require for their reaction?

A

Molecular oxygen, NADPHm NADPH-P450 reductase

107
Q

What are the main features of a solute carrier transporters?

A
  • Non-selective transporters
  • Highly expressed in liver and kidney
  • Can influence drug elimination
    • e.g. blood into urine
108
Q

Define

Agonist

A

a substance which initiates a physiological response when combined with a receptor

109
Q

Definition

a strategy of the essential importance for chemistry and pharmacy, based on the idea that when we change a structure of a molecule then also the activity or property of the substance will be modified

A

Quantitative structure activity relationships (QSAR)

110
Q

Definition

the volume of plasma cleared of drug per unit time

A

Clearance (CL)

111
Q

Definition

the degree to which a substance tends to combine with another

A

Affinity

112
Q

Define

Quantitative structure activity relationships (QSAR)

A

a strategy of the essential importance for chemistry and pharmacy, based on the idea that when we change a structure of a molecule then also the activity or property of the substance will be modified

113
Q

Define

Plasma protein binding (PPB)

A

the degree to which medications attach to proteins within the blood

114
Q

Define

Hit-to-lead

A

a stage in early drug discovery where small molecule hits from a high throughput screen (HTS) are evaluated and undergo limited optimization to identify promising lead compounds

115
Q

What are the characteristics of drugs that move through cell membrane via facilitated diffusion?

A

They need to be similar to an endogenous molecule

116
Q

Define

Clearance (CL)

A

the volume of plasma cleared of drug per unit time

117
Q

Definition

any chemical substance (other than a nutrient or essential dietary ingredient) that brings about a change in biological function

A

Drug

118
Q

What are the limitations of toxicity testing in animals?

A

Extrapolation of toxicity from animals to humans is not completely reliable

Rare adverse effects not likely to be detected

  • Rodents predictive for 43% of human toxicity
  • Non-rodents predictive for 63% of human toxicity
  • Rodent + non-rodents predictive for 71% of human toxicity
119
Q

Define

Lipinski Rule of 5

A

a rule of thumb to evaluate druglikeness or determine if a chemical compound with a certain pharmacological or biological activity has chemical properties and physical properties that would make it a likely orally active drug in humans

120
Q

What is the main objective of the clinical development phase?

A

Assessing safety and efficacy

121
Q

Definition

a widely employed method that uses bacteria to test whether a given chemical can cause mutations in the DNA of the test organism. More formally, it is a biological assay to assess the mutagenic potential of chemical compounds

A

Ames test

122
Q

Define

Toxicogenomic

A

a subdiscipline of pharmacology that deals with the collection, interpretation, and storage of information about gene and protein activity within a particular cell or tissue of an organism in response to exposure to toxic substances

123
Q

Definition

involves chemical reactions such as oxidation (most common), reduction and hydrolysis in order to inactivate drugs

A

Phase I enzymatic metabolism

124
Q

What are the three strategies for finding new drug targets?

A
  1. Analysis of pathophysiology
  2. Analysis of mechanism of action of existing therapeutic drugs
  3. Genomic approaches
125
Q

Define

Cytochrome P450

A

a superfamily of enzymes containing heme as a cofactor that function as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various compounds, as well as for hormone synthesis and breakdown

126
Q

Definition

compares two or more treatments. Participants are randomly assigned to either group, treatments are administered, and then the results are compared

A

Parallel design

127
Q

If a drug very easily moes out of the plasma compartment (e.g. very lipophilic molecule), the volume it is distributed is __________ plasma volume

A

If a drug very easily moes out of the plasma compartment (e.g. very lipophilic molecule), the volume it is distributed is much greater than plasma volume

128
Q

Definition

a subdiscipline of pharmacology that deals with the collection, interpretation, and storage of information about gene and protein activity within a particular cell or tissue of an organism in response to exposure to toxic substances

A

Toxicogenomic

129
Q

Definition

what the drug does to the body

A

Pharmacodynamics

130
Q

Definition

a stage in early drug discovery where small molecule hits from a high throughput screen (HTS) are evaluated and undergo limited optimization to identify promising lead compounds

A

Hit-to-lead

131
Q

How do cytochrome P450 molecules differ?

A
  • Amino acid sequence
  • Sensitivity to inhibitors & inducing agents
  • Substrate specificity
132
Q

What factors will influence the movement of dugs across membranes?

A

Size

Polarity

Lipophilicity

133
Q

What are the design features of a chronic carcinogenic effects test? What information can be obtained?

A
134
Q

Define

In vitro profiling

A

involves the screening of compounds against a broad range of targets (receptors, ion channels, enzymes and transporters) that are distinct from the intended therapeutic target (or targets) in order to identify specific molecular interactions that may cause ADRs in humans

135
Q

Definition

involves the screening of compounds against a broad range of targets (receptors, ion channels, enzymes and transporters) that are distinct from the intended therapeutic target (or targets) in order to identify specific molecular interactions that may cause ADRs in humans

A

In vitro profiling

136
Q

Definition

time taken for the amount of drug in the plasma to fall by half

A

Plasma half-life (t1/2)

137
Q

Definition

the fraction of drug in an animal that is eliminated per unit of time, e.g., fraction/h

A

Rate of elimination (RE)

138
Q

Definition

a family of more than 300 membrane-bound proteins that facilitate the transport of a wide array of substrates across biological membranes — have important roles in physiological processes ranging from the cellular uptake of nutrients to the absorption of drugs and other xenobiotics

A

Solute carrier transporters

139
Q

The Vd of a drug was found to be approximately 0.55 L/kg. Where has the drug distributed?

A

Drug distributed throughout total body water

140
Q

Define

Rate of elimination (RE)

A

the fraction of drug in an animal that is eliminated per unit of time, e.g., fraction/h

141
Q

Where are p-glycoproteins typically located?

A

Primarily on epithelial cells with excretory roles:

  • renal tubular brush border membranes
  • bile canaliculi
  • brain microvessels
  • GIT
142
Q

Define

Ames test

A

a widely employed method that uses bacteria to test whether a given chemical can cause mutations in the DNA of the test organism. More formally, it is a biological assay to assess the mutagenic potential of chemical compounds

143
Q

Which processes are responsible for drug elimination?

A
144
Q

Define

Drug

A

any chemical substance (other than a nutrient or essential dietary ingredient) that brings about a change in biological function

145
Q

Why do you incubate the drug with liver enzyme/fraction homogenate prior to Ames test?

A
  • Prodrugs (activated by the liver)
  • Active drugs (metabolised by liver)
    • Are metabolites toxic?
146
Q

The Vd of a drug was found to be approximately 0.05 L/kg. Where has the drug distributed and what are the characteristics of the drug?

A

Drug is retained in the vascular ‘compartment’

Drug has high molecular weight/extensive protein binding

147
Q

Definition

a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity

A

Potency

148
Q

Define

Comparator

A

the current drug on the market being used to treat a specific condition

149
Q

Is drug-induced diabetes an example of acute or chronic animal model?

A

Chronic

150
Q

Definition

a large superfamily of membrane proteins with diverse functions (Holland et al. 2003). They convert the energy gained from ATP hydrolysis into trans-bilayer movement of substrates either into the cytoplasm (import) or out of the cytoplasm (export)

A

ATP-binding cassette (ABC) transporters

151
Q

Define

Open-label

A

A term used to describe the situation when both the researcher and the participant in a research study know the treatment the participant is receiving

152
Q

Definition

a way of describing how the body uses and breaks down some medicines. While the rate at which the body eliminates most drugs is proportional to the concentration administered, known as first order kinetics, drugs that work by this mechanism work at a predictable, constant rate

A

Zero order kinetics

153
Q

What are the two most common targets of drugs?

A

GPCRs and enzymes

154
Q

Define

ATP-binding cassette (ABC) transporters

A

a large superfamily of membrane proteins with diverse functions (Holland et al. 2003). They convert the energy gained from ATP hydrolysis into trans-bilayer movement of substrates either into the cytoplasm (import) or out of the cytoplasm (export)

155
Q

What would the volume of distribution for very large molecules or molecules with high PPB be similar to?

A

If a drug does not readily move out of the plasma compartment, the volume it is distributed in is similar to plasma volume (~0.05L/kg)

156
Q

Definition

the current drug on the market being used to treat a specific condition

A

Comparator

157
Q

Definition

the first step in making urine. It is the process that your kidneys use to filter excess fluid and waste products out of the blood into the urine collecting tubules of the kidney, so they may be eliminated from your body

A

Glomerular filtration

158
Q

On average how many new molecular entities (NMEs; drugs) are approved per year?

a) 10
b) 30
c) 50
d) 70

A

On average how many new molecular entities (NMEs; drugs) are approved per year?

a) 10

b) 30
c) 50
d) 70

159
Q

What does in vitro profiling reveal?

A
  • Do molecular and cellular effects translate to predicted pharmacological action in intact tissue?
  • Off target effects?
  • Does potency of compound at molecular level, tissue level and whole animal correlate?
160
Q

The average time to market of a new drug is:

a) 2-5 years
b) 8-11 years
c) 12-15 years
d) 16-19 years

A

The average time to market of a new drug is:

a) 2-5 years
b) 8-11 years

c) 12-15 years

d) 16-19 years

161
Q

What type of carrier mediated transporter are p-glycoproteins?

A

ATP-binding cassette (ABC) transporter

162
Q

Is elevated maze test to test anxiolytic drugs an example of acute or chronic animal model?

A

Acute

163
Q

Define

Tubular secretion

A

the transfer of materials from peritubular capillaries to the renal tubular lumen; it is the opposite process of reabsorption

164
Q

What do pharmacophores contain?

A

Pharmacophores contain the chemical structural features which are essential for “activity” at the receptor

165
Q
A
166
Q

Definition

a design in which participants receive two or more sequential interventions in a random order in separate treatment periods

A

Cross-over design

167
Q

Why is Phase I drug metabolism a potential site for drug-drug interactions?

A

The enzymes involved have broad substrate specificity

168
Q

What is the main objective of preclinical development?

A

Assessing safety

169
Q

Definition

a medication or compound that, after administration, is metabolized (i.e., converted within the body) into a pharmacologically active drug

A

Prodrug

170
Q

What are the two most common reasons that drugs fail in clinical trials?

A

Side-effects

Lack of efficacy in humans

171
Q

Definition

a part of a molecular structure that is responsible for a particular biological or pharmacological interaction that it undergoes

A

Pharmacophores

172
Q

Define

Candidate drug

A

a compound (small molecule, antibody, etc.) with strong therapeutic potential and whose activity and specificity have been optimised

173
Q

True or False:

All drugs with zero order kinetics are metabolised

A

True

174
Q

Definition

m involves reactions that chemically change the drug or phase 1 metabolites into compounds that are soluble enough to be excreted in urine. In these reactions, the molecule (drug or metabolite) is attached to an ionisable grouping

A

Phase II enzymatic metabolism

175
Q

Which two mechanisms enable drug elimination?

A

Metabolism

Excretion

176
Q

Define

Pharmacodynamics

A

what the drug does to the body

177
Q

Define

Cross-over design

A

a design in which participants receive two or more sequential interventions in a random order in separate treatment periods

178
Q

Define

Endogenous

A

growing or originating from within an organism

179
Q

Define

P-glycoproteins

A

a plasma membrane protein which acts as a localized drug transport mechanism, actively exporting drugs out of the cell

180
Q

What is plasma half-life a major determinant of?

A

Dosing frequency

Time to eliminate the drug (4-5 t1/2s)

Time requires to reach steady state with repeat dosing (4-5 t1/2s)

181
Q

Define

Pharmacokinetics

A

what the body does to the drug

182
Q

Define

Pharmacokinetics

A

what the body does to the drug

183
Q

Define

Xenobiotics

A

a chemical substance found within an organism that is not naturally produced or expected to be present within the organism

184
Q

What does drug clearance by the renal system depend on?

A

[drug] in urine

Urine flow rate

[free drug] in plasma

185
Q

What are the elimination characteristics of drugs that are dictated by first order kinetics?

A
  • Rate of elimination is driven by Cp
  • Constant/repeated doing will achieve a steady state Cp
  • Time to reach steady state is determine by half-life
  • Time for “removal” is determined by half-life
186
Q

Definition

growing or originating from within an organism

A

Endogenous

187
Q

What are the characteristics of plasma protein binding for most drugs?

A
  • [free drug] << [protein]
  • Therefore [DP} depends on [D]
  • Therefore fraction bound is constant
188
Q

What type of drugs tend to be excluded by cell membranes?

A

Very polar drugs

189
Q

Definition

Initialism of absorption, distribution, metabolism, excretion, toxicity: A set of test categories used together in drug discovery to provide insight into how a pharmaceutical drug interacts with the body as a whole

A

ADMET

190
Q

The Vd of a drug was found to be approximately 0.2 L/kg. Where has the drug distributed and what are the characteristics of the drug?

A

Drug restricted to extracellular fluid

Drug has low molecular weight but hydrophilic/lipophobic

191
Q

Which type of drug metabolism does prodrugs exploit?

A

Phase I

192
Q

Define

Maximum tolerated dose (MTD)

A

the highest dose of a medicine or treatment that will produce the desired effect without resulting in unacceptable side effects

193
Q

Define

Carcinogenic effects

A

increase the risk of cancer by altering cellular metabolism or damaging DNA directly in cells, which interferes with biological processes, and induces the uncontrolled, malignant division, ultimately leading to the formation of tumors

194
Q

Define

First order kinetics

A

a way of describing how the body uses and breaks down some medicines. It is a concentration-dependent process (i.e. the higher the concentration, the faster the clearance)

195
Q

Define

Parallel design

A

compares two or more treatments. Participants are randomly assigned to either group, treatments are administered, and then the results are compared

196
Q

True or False:

For most drugs, plasma half-life is constant

A

True

197
Q

Definition

the branch of genetics concerned with determining the likely response of an individual to therapeutic drugs.

A

Pharmacogenomics

198
Q

What happens if the drug plasma concentration is higher than the therapeutic window?

A

Toxicity

199
Q

Define

Phase I enzymatic metabolism

A

involves chemical reactions such as oxidation (most common), reduction and hydrolysis in order to inactivate drugs

200
Q

How does analysis of mechanism of action of existing therapeutic drugs help us find new drug targets?

A

Work ‘backwards’ from known action to mechanism

201
Q

On average, how many innovative targets are commercialised per year?

a) 2-3
b) 4-6
c) 6-7
d) 8-10

A

On average, how many innovative targets are commercialised per year?

a) 2-3

b) 4-6
c) 6-7
d) 8-10

202
Q

Define

ADMET

A

Initialism of absorption, distribution, metabolism, excretion, toxicity: A set of test categories used together in drug discovery to provide insight into how a pharmaceutical drug interacts with the body as a whole

203
Q
A
204
Q

True or False:

Phase II drug metabolism is saturable

A

True

205
Q

Define

Randomisation

A

the process of assigning clinical trial participants to treatment groups such that each participation has a known (usually equal) chance of being assigned to any of the groups

206
Q

Definition

a substance which initiates a physiological response when combined with a receptor

A

Agonist

207
Q

What are the characteristics of a perfect drug?

A
  • Orally bioavailable
  • Low/no side-effects
  • High selectivity
  • Not excreted quickly (pharmacokinetics)
  • Good solubility (distribution)
  • ADMET
  • Cheap and easy to synthesis
208
Q

How do majority of drugs move across a membrane? What characteristics do these drugs have?

A

Simple diffusion

  • Small
  • Lipophilic
209
Q

What factors influence drug distribution?

A
  • Movement of drug across cell membranes
  • Binding to plasma proteins
  • Blood flow to particular regions
  • Binding to extravascular sites including tissues
210
Q

Absorption, distribution, metabolism and excretion make up which phase of drug pharmacology?

A

Pharmacokinetic phase

211
Q

What are the four main sources of new drugs?

A
  1. Screening of natural products
  2. Serendipity
  3. Rational design
  4. Screening of chemical libraries
212
Q

What are the characteristics of the metabolite of a phase II metabolism reaction?

A
  • Pharmacologically inactive (usually)
  • Less lipid soluble
  • Excreted in urine or into bile
213
Q

What type of drugs tend to be concentrated in cells enriched in fat?

A

Lipophillic drugs

214
Q

Define

Solute carrier transporters

A

a family of more than 300 membrane-bound proteins that facilitate the transport of a wide array of substrates across biological membranes — have important roles in physiological processes ranging from the cellular uptake of nutrients to the absorption of drugs and other xenobiotics

215
Q

What is the important family of enzymes involved in Phase I drug metabolism?

A

Cytochrome P450

216
Q

What does drug clearance by the liver depend on?

A

Hepatic blood flow

Intrinsic clearance

[free drug] in plasma

217
Q

Define

Affinity

A

the degree to which a substance tends to combine with another

218
Q

Define

Enzyme induction

A

a process in which a molecule (e.g. a drug) induces (i.e. initiates or enhances) the expression of an enzyme

219
Q

What does the total amount eliminated via the kidneys depend on?

A

Amount filtered + amount secreted - amount reabsorbed

220
Q

Define

Plasma half-life (t1/2)

A

time taken for the amount of drug in the plasma to fall by half

221
Q

Definition

recent scientific methods relevant to the field of chemistry and biology, in which hundreds of thousands of experimental samples are subjected to simultaneous testing under given conditions

A

High-throughput screening (HTS)

222
Q

Where do very large drugs tend to distribute to?

A

Circulation

223
Q

What are the disadvantages of fast-tracking a clinical trial?

A
  • Unknown side-effects
  • Drug could be unsafe
224
Q

True or False:

Phase I drug metabolism is potentially saturable

A

True

225
Q

Define

Enterohepatic recycling

A

a feedback mechanism resulting from the combined roles of the liver and intestine

226
Q

Definition

a drug’s ability to preferentially produce a particular effect and is related to the structural specificity of drug binding to receptors

A

Selectivity

227
Q

Definition

what the body does to the drug

A

Pharmacokinetics

228
Q

True or False:

The dosage interval affects the mean steady state concentration achieved

A

False

The dosage interval does not affect the mean steady state concentration achieved

229
Q

What type of drugs enter cells via pinocytosis?

A

Large drugs

230
Q

Define

Systemic toxicity

A

toxic effects that occur at multiple sites

231
Q

How do large drugs enter a cell?

A

Pinocytosis

232
Q

What factors impact drug clearance?

A
  • Movement of drug across cell membranes
  • Urine flow rate/GFR
  • [free drug] in plasma
  • Hepatic blood flow/intrinsic hepatic clearance
  • Activity of metabolising enzymes
233
Q

What is rate of elimination (RE) equal to?

A

RE = CL x [plasma]

234
Q

Define

Hit candidate

A

a drug that has shown affinity for a specific molecular target

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