Drugs and Therapy Flashcards
Define
Glomerular filtration
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
What are testing in the four phases of clinical development?
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
In order to achieve a steady state, maintenance dose rate (DR) must equal what?
RE
i.e. DR = CL x target Cp
Definition
one in which neither the participants nor the experimenters know who is receiving a particular treatment
Double-blind
Define
Potency
a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity
A drug with a large therapeutic window is said to be ______ than a drug with a small therapeutic window
A drug with a large therapeutic window is said to be safer than a drug with a small therapeutic window
What are p-glycoproteins involved in?
Uptake and efflux of a range of drugs
- Influence plasma and tissue [drug]
What are the advantages of fast-tracking a clinical trial?
- Cheaper
- Demand (urgent disease)
- Hope
- Crisis resolution
- Cancer (no alternative treatment)
What is structure based drug designed?
Using the structure of the receptor target itself to deduce the chemical structure that would interact with the receptor
Is seizures induced by electrical stimulation an example of acute or chronic animal model?
Acute
Define
Teratogenic effects
an agent that can disturb the development of the embryo or fetus
Define
Volume of distribution (Vd)
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
Definition
the development of adverse effects as the result of long term exposure to a toxicant or other stressor
Chronic toxicity
Definition
an inert substance or treatment which is designed to have no therapeutic value
Placebo
Definition
the highest dose of a medicine or treatment that will produce the desired effect without resulting in unacceptable side effects
Maximum tolerated dose (MTD)
What does drug metabolism do and what does it depend on?
- 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
True or False:
Phase II drug metabolism is not considered important for drug-drug interactions
True
What does the degree of plasma protein binding depend on?
- [free drug]
- affinity of drug for binding sites
- [plasma protein]
Definition
a substance which interferes with or inhibits the physiological action of another
Antagonist
Illustrate the Ames test
Define
Chronic toxicity
the development of adverse effects as the result of long term exposure to a toxicant or other stressor
Define
Antagonist
a substance which interferes with or inhibits the physiological action of another
What are the three main categories of drug toxicity that need to be explored?
Systemic toxicity
Carcinogenic effects
Teratogenic effects
Definition
a drug that has shown affinity for a specific molecular target
Hit candidate
Definition
a compound (small molecule, antibody, etc.) with strong therapeutic potential and whose activity and specificity have been optimised
Candidate drug
True or False:
It is important to conduct animal studies in all stages of lead discovery and optimisation
True
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
Volume of distribution (Vd)
Definition
an agent that can disturb the development of the embryo or fetus
Teratogenic effects
Definition
substances which alter the catalytic action of the enzyme and consequently slow down, or in some cases, stop catalysis
Enzyme inhibition
Definition
Highest dose at which there was not an observed toxic or adverse effect
No (observed) adverse effect level (NOAEL)
Define
High-throughput screening (HTS)
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 Vd > 0.55L/kg indicates what?
The drug is actively concentrating in certain areas
Filtering a primary hit candidate into validated hit candidates (secondary screen) involved the drug demonstrating what?
Confirm affinity/potency/selectivity
What is a hit candidate?
A drug that successfully bind the target
Definition
what the body does to the drug
Pharmacokinetics
Definition
the degree to which medications attach to proteins within the blood
Plasma protein binding (PPB)
What factors affect drug distribution?
- 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
Definition
a feedback mechanism resulting from the combined roles of the liver and intestine
Enterohepatic recycling
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
Open-label
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
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
Definition
the transfer of materials from peritubular capillaries to the renal tubular lumen; it is the opposite process of reabsorption
Tubular secretion
Define
Single-blind
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
What does knowledge of a drugs pharmacokinetics enable?
- 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
The average cost of R&D for a new drug is:
a) $50 million
b) $400 million
c) $1 billion
d) $2 billion
The average cost of R&D for a new drug is:
a) $50 million
b) $400 million
c) $1 billion
d) $2 billion
Define
Zero order kinetics
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
When wouldn’t healthy volunteers be used in a Phase I trial?
When a drug has known toxicity (i.e. chemotherapy)
Urgent need/fast-tracking (COVID-19)
What are the main features of a ATP-binding cassette (ABC) transporters?
- Active transporters involved in cell efflux
- Includes p-glycoproteins
Define
Prodrug
a medication or compound that, after administration, is metabolized (i.e., converted within the body) into a pharmacologically active drug
Definition
toxic effects that occur at multiple sites
Systemic toxicity
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
Single-blind
What is the plasma half-life difference between zero and first order drug elimination?
Zero order: Half-life will vary with plasma []
First order: Half-life is constant
Where does Phase I drug metabolism occur?
Liver, but also in other tissues
Define
Enzyme inhibition
substances which alter the catalytic action of the enzyme and consequently slow down, or in some cases, stop catalysis
Define
Pharmacophores
a part of a molecular structure that is responsible for a particular biological or pharmacological interaction that it undergoes
How does analysis of pathophysiology help us find new drug targets?
Understanding of pathways involved in disease determines novel target
Define
Placebo
an inert substance or treatment which is designed to have no therapeutic value
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
Loading dose (LD)
How can we validate a drug target?
By knocking it out and seeing the result
Filtering a screening library into a primary hit candidate (primary screen) involves the drug demonstrating what?
Activity against the target (affinity)
Why is a loading dose sometimes necessary?
Some drugs have a very long time to achieve steady state
What does QSAR involve?
Using a pharmacophore and relating physical properties of a series of compounds
What is [drug] plasma (Cp) equal to?
Cp = dose rate (DR) / Clearance
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
Lead compound
What happens if the drug plasma concentration is lower than the therapeutic window?
No benefit - unnecessary risk
Predict the difference in renal clearance between:
- a very lipophilic drug
- a highly ionised drug
- a biological (i.e. large molecule)
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
How do you calculate volume of distribution (Vd)?
Vd = dose / [plasma]
What type of drugs usually warrant a loading dose (LD)?
Usually needed for drugs with high volume of distribution
Other than urine and faeces, what are some routes of excretion of drugs?
Lungs, sweat, saliva, mucous, tears and breast milk
What are the two types of enzymatic metabolism reactions?
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
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)
First order kinetics
Define
Phase II enzymatic metabolism
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
What are the design features of a acute systemic toxicity test? What information can be obtained?
Define
Selectivity
a drug’s ability to preferentially produce a particular effect and is related to the structural specificity of drug binding to receptors
True or False:
Dosage interval affects the rate that the mean steady state concentration is achieved
False
Dosage interval does not affect the rate that the mean steady state concentration is achieved
What occurs when drug interaction results in enzyme induction?
Some drugs can increase activity/levels of the enzymes that metabolism them (e.g. alcohol tolerance)
Why does a paracentamol OD cause hepatotoxicity?
The conjugates get overwhelmed causing a build up of the toxic NAPQI product
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
Lipinski Rule of 5
Definition
a plasma membrane protein which acts as a localized drug transport mechanism, actively exporting drugs out of the cell
P-glycoproteins
How do you calculate a loading dose?
LD = Vd x target [plasma]
Definition
a chemical substance found within an organism that is not naturally produced or expected to be present within the organism
Xenobiotics
Define
Loading dose (LD)
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
Where do lipophillic drugs tend to distribute to?
Cells enriched with fat
What does in vivo profiling reveal?
- 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
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
Cytochrome P450
What are the two main types of transporters involved in carrier mediated transport?
Solute carrier transporters
ATP-binding cassette (ABS) transporters
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
Randomisation
What are the design features of a teratogenic effect test? What information can be obtained?
True or False:
Protein-bound molecules are not available to extort pharmacological effects
True
Definition
a process in which a molecule (e.g. a drug) induces (i.e. initiates or enhances) the expression of an enzyme
Enzyme induction
What occurs when drug interaction results in enzyme inhibition?
The drugs are metabolised by the same enzyme. If administered together, they will compete for the metabolising enzyme
True or False:
Phase I drug metabolism is a potential site for drug-drug interactions
True
Define
Lead compound
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
No (observed) adverse effect level (NOAEL)
Highest dose at which there was not an observed toxic or adverse effect
Define
Double-blind
one in which neither the participants nor the experimenters know who is receiving a particular treatment
Is surgically-induced hypertension an example of acute or chronic animal model?
Chronic
Define
Pharmacogenomics
the branch of genetics concerned with determining the likely response of an individual to therapeutic drugs.
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
Carcinogenic effects
Where does Phase II drug metabolism usually occur?
Liver
The elimination of drugs with zero/first order kinetics is independent of [drug] plasma
The elimination of drugs with zero order kinetics is independent of [drug] plasma
What is the average Total Body Water (TBW) volume of a 70kg man?
40L
Where do very polar drugs tend to distribute to?
Circulation and interstitial fluid
What are the design features of a chronic systemic toxicity test? What information can be obtained?
What type of drugs tend to be confined to the circulation?
Very large molecules
What does a pharmacophore model define?
The structure necessary for drug binding (and activation or blockade)
What do cytochrome P450 enzymes require for their reaction?
Molecular oxygen, NADPHm NADPH-P450 reductase
What are the main features of a solute carrier transporters?
- Non-selective transporters
- Highly expressed in liver and kidney
- Can influence drug elimination
- e.g. blood into urine
Define
Agonist
a substance which initiates a physiological response when combined with a receptor
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
Quantitative structure activity relationships (QSAR)
Definition
the volume of plasma cleared of drug per unit time
Clearance (CL)
Definition
the degree to which a substance tends to combine with another
Affinity
Define
Quantitative structure activity relationships (QSAR)
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
Define
Plasma protein binding (PPB)
the degree to which medications attach to proteins within the blood
Define
Hit-to-lead
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
What are the characteristics of drugs that move through cell membrane via facilitated diffusion?
They need to be similar to an endogenous molecule
Define
Clearance (CL)
the volume of plasma cleared of drug per unit time
Definition
any chemical substance (other than a nutrient or essential dietary ingredient) that brings about a change in biological function
Drug
What are the limitations of toxicity testing in animals?
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
Define
Lipinski Rule of 5
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
What is the main objective of the clinical development phase?
Assessing safety and efficacy
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
Ames test
Define
Toxicogenomic
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
Definition
involves chemical reactions such as oxidation (most common), reduction and hydrolysis in order to inactivate drugs
Phase I enzymatic metabolism
What are the three strategies for finding new drug targets?
- Analysis of pathophysiology
- Analysis of mechanism of action of existing therapeutic drugs
- Genomic approaches
Define
Cytochrome P450
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
Definition
compares two or more treatments. Participants are randomly assigned to either group, treatments are administered, and then the results are compared
Parallel design
If a drug very easily moes out of the plasma compartment (e.g. very lipophilic molecule), the volume it is distributed is __________ plasma volume
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
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
Toxicogenomic
Definition
what the drug does to the body
Pharmacodynamics
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
Hit-to-lead
How do cytochrome P450 molecules differ?
- Amino acid sequence
- Sensitivity to inhibitors & inducing agents
- Substrate specificity
What factors will influence the movement of dugs across membranes?
Size
Polarity
Lipophilicity
What are the design features of a chronic carcinogenic effects test? What information can be obtained?
Define
In vitro profiling
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
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
In vitro profiling
Definition
time taken for the amount of drug in the plasma to fall by half
Plasma half-life (t1/2)
Definition
the fraction of drug in an animal that is eliminated per unit of time, e.g., fraction/h
Rate of elimination (RE)
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
Solute carrier transporters
The Vd of a drug was found to be approximately 0.55 L/kg. Where has the drug distributed?
Drug distributed throughout total body water
Define
Rate of elimination (RE)
the fraction of drug in an animal that is eliminated per unit of time, e.g., fraction/h
Where are p-glycoproteins typically located?
Primarily on epithelial cells with excretory roles:
- renal tubular brush border membranes
- bile canaliculi
- brain microvessels
- GIT
Define
Ames test
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
Which processes are responsible for drug elimination?
Define
Drug
any chemical substance (other than a nutrient or essential dietary ingredient) that brings about a change in biological function
Why do you incubate the drug with liver enzyme/fraction homogenate prior to Ames test?
- Prodrugs (activated by the liver)
- Active drugs (metabolised by liver)
- Are metabolites toxic?
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?
Drug is retained in the vascular ‘compartment’
Drug has high molecular weight/extensive protein binding
Definition
a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity
Potency
Define
Comparator
the current drug on the market being used to treat a specific condition
Is drug-induced diabetes an example of acute or chronic animal model?
Chronic
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)
ATP-binding cassette (ABC) transporters
Define
Open-label
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
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
Zero order kinetics
What are the two most common targets of drugs?
GPCRs and enzymes
Define
ATP-binding cassette (ABC) transporters
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)
What would the volume of distribution for very large molecules or molecules with high PPB be similar to?
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)
Definition
the current drug on the market being used to treat a specific condition
Comparator
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
Glomerular filtration
On average how many new molecular entities (NMEs; drugs) are approved per year?
a) 10
b) 30
c) 50
d) 70
On average how many new molecular entities (NMEs; drugs) are approved per year?
a) 10
b) 30
c) 50
d) 70
What does in vitro profiling reveal?
- 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?
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
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
What type of carrier mediated transporter are p-glycoproteins?
ATP-binding cassette (ABC) transporter
Is elevated maze test to test anxiolytic drugs an example of acute or chronic animal model?
Acute
Define
Tubular secretion
the transfer of materials from peritubular capillaries to the renal tubular lumen; it is the opposite process of reabsorption
What do pharmacophores contain?
Pharmacophores contain the chemical structural features which are essential for “activity” at the receptor
Definition
a design in which participants receive two or more sequential interventions in a random order in separate treatment periods
Cross-over design
Why is Phase I drug metabolism a potential site for drug-drug interactions?
The enzymes involved have broad substrate specificity
What is the main objective of preclinical development?
Assessing safety
Definition
a medication or compound that, after administration, is metabolized (i.e., converted within the body) into a pharmacologically active drug
Prodrug
What are the two most common reasons that drugs fail in clinical trials?
Side-effects
Lack of efficacy in humans
Definition
a part of a molecular structure that is responsible for a particular biological or pharmacological interaction that it undergoes
Pharmacophores
Define
Candidate drug
a compound (small molecule, antibody, etc.) with strong therapeutic potential and whose activity and specificity have been optimised
True or False:
All drugs with zero order kinetics are metabolised
True
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
Phase II enzymatic metabolism
Which two mechanisms enable drug elimination?
Metabolism
Excretion
Define
Pharmacodynamics
what the drug does to the body
Define
Cross-over design
a design in which participants receive two or more sequential interventions in a random order in separate treatment periods
Define
Endogenous
growing or originating from within an organism
Define
P-glycoproteins
a plasma membrane protein which acts as a localized drug transport mechanism, actively exporting drugs out of the cell
What is plasma half-life a major determinant of?
Dosing frequency
Time to eliminate the drug (4-5 t1/2s)
Time requires to reach steady state with repeat dosing (4-5 t1/2s)
Define
Pharmacokinetics
what the body does to the drug
Define
Pharmacokinetics
what the body does to the drug
Define
Xenobiotics
a chemical substance found within an organism that is not naturally produced or expected to be present within the organism
What does drug clearance by the renal system depend on?
[drug] in urine
Urine flow rate
[free drug] in plasma
What are the elimination characteristics of drugs that are dictated by first order kinetics?
- 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
Definition
growing or originating from within an organism
Endogenous
What are the characteristics of plasma protein binding for most drugs?
- [free drug] << [protein]
- Therefore [DP} depends on [D]
- Therefore fraction bound is constant
What type of drugs tend to be excluded by cell membranes?
Very polar drugs
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
ADMET
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?
Drug restricted to extracellular fluid
Drug has low molecular weight but hydrophilic/lipophobic
Which type of drug metabolism does prodrugs exploit?
Phase I
Define
Maximum tolerated dose (MTD)
the highest dose of a medicine or treatment that will produce the desired effect without resulting in unacceptable side effects
Define
Carcinogenic effects
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
Define
First order kinetics
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)
Define
Parallel design
compares two or more treatments. Participants are randomly assigned to either group, treatments are administered, and then the results are compared
True or False:
For most drugs, plasma half-life is constant
True
Definition
the branch of genetics concerned with determining the likely response of an individual to therapeutic drugs.
Pharmacogenomics
What happens if the drug plasma concentration is higher than the therapeutic window?
Toxicity
Define
Phase I enzymatic metabolism
involves chemical reactions such as oxidation (most common), reduction and hydrolysis in order to inactivate drugs
How does analysis of mechanism of action of existing therapeutic drugs help us find new drug targets?
Work ‘backwards’ from known action to mechanism
On average, how many innovative targets are commercialised per year?
a) 2-3
b) 4-6
c) 6-7
d) 8-10
On average, how many innovative targets are commercialised per year?
a) 2-3
b) 4-6
c) 6-7
d) 8-10
Define
ADMET
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
True or False:
Phase II drug metabolism is saturable
True
Define
Randomisation
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
Definition
a substance which initiates a physiological response when combined with a receptor
Agonist
What are the characteristics of a perfect drug?
- Orally bioavailable
- Low/no side-effects
- High selectivity
- Not excreted quickly (pharmacokinetics)
- Good solubility (distribution)
- ADMET
- Cheap and easy to synthesis
How do majority of drugs move across a membrane? What characteristics do these drugs have?
Simple diffusion
- Small
- Lipophilic
What factors influence drug distribution?
- Movement of drug across cell membranes
- Binding to plasma proteins
- Blood flow to particular regions
- Binding to extravascular sites including tissues
Absorption, distribution, metabolism and excretion make up which phase of drug pharmacology?
Pharmacokinetic phase
What are the four main sources of new drugs?
- Screening of natural products
- Serendipity
- Rational design
- Screening of chemical libraries
What are the characteristics of the metabolite of a phase II metabolism reaction?
- Pharmacologically inactive (usually)
- Less lipid soluble
- Excreted in urine or into bile
What type of drugs tend to be concentrated in cells enriched in fat?
Lipophillic drugs
Define
Solute carrier transporters
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
What is the important family of enzymes involved in Phase I drug metabolism?
Cytochrome P450
What does drug clearance by the liver depend on?
Hepatic blood flow
Intrinsic clearance
[free drug] in plasma
Define
Affinity
the degree to which a substance tends to combine with another
Define
Enzyme induction
a process in which a molecule (e.g. a drug) induces (i.e. initiates or enhances) the expression of an enzyme
What does the total amount eliminated via the kidneys depend on?
Amount filtered + amount secreted - amount reabsorbed
Define
Plasma half-life (t1/2)
time taken for the amount of drug in the plasma to fall by half
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
High-throughput screening (HTS)
Where do very large drugs tend to distribute to?
Circulation
What are the disadvantages of fast-tracking a clinical trial?
- Unknown side-effects
- Drug could be unsafe
True or False:
Phase I drug metabolism is potentially saturable
True
Define
Enterohepatic recycling
a feedback mechanism resulting from the combined roles of the liver and intestine
Definition
a drug’s ability to preferentially produce a particular effect and is related to the structural specificity of drug binding to receptors
Selectivity
Definition
what the body does to the drug
Pharmacokinetics
True or False:
The dosage interval affects the mean steady state concentration achieved
False
The dosage interval does not affect the mean steady state concentration achieved
What type of drugs enter cells via pinocytosis?
Large drugs
Define
Systemic toxicity
toxic effects that occur at multiple sites
How do large drugs enter a cell?
Pinocytosis
What factors impact drug clearance?
- Movement of drug across cell membranes
- Urine flow rate/GFR
- [free drug] in plasma
- Hepatic blood flow/intrinsic hepatic clearance
- Activity of metabolising enzymes
What is rate of elimination (RE) equal to?
RE = CL x [plasma]
Define
Hit candidate
a drug that has shown affinity for a specific molecular target
