Podcast
Questions and Answers
What is the primary focus of rational drug use?
What is the primary focus of rational drug use?
- Following the latest trends in pharmaceutical marketing
- Minimizing the cost of medication
- Prescribing the newest medications available
- Using medications to achieve a therapeutic goal (correct)
Which of the following is a key aspect of rational drug use?
Which of the following is a key aspect of rational drug use?
- Prioritizing brand-name drugs over generics
- Ensuring the patient receives the right drug for their clinical needs (correct)
- Administering the highest dose possible for quick results
- Recommending medications based on popularity
Why is understanding the mechanism of a disease important for curing it?
Why is understanding the mechanism of a disease important for curing it?
- It ensures compliance with FDA regulations
- It allows for targeted interventions to correct the underlying problem (correct)
- It helps in marketing drugs more effectively
- It helps in identifying potential side effects of medications
What is a common limitation of many drugs?
What is a common limitation of many drugs?
Approximately how many novel drugs were approved by the FDA in 2022?
Approximately how many novel drugs were approved by the FDA in 2022?
A significant percentage of novel drugs approved in 2022 were intended for what?
A significant percentage of novel drugs approved in 2022 were intended for what?
What is a potential consequence of polypharmacy, especially in elderly patients?
What is a potential consequence of polypharmacy, especially in elderly patients?
What is the estimated number of people harmed annually due to medication errors?
What is the estimated number of people harmed annually due to medication errors?
What does the core scaffold of a molecule primarily do?
What does the core scaffold of a molecule primarily do?
What structural feature is commonly found in core scaffolds?
What structural feature is commonly found in core scaffolds?
If a group on a molecule is removed and the molecule loses activity, what does this indicate about the group?
If a group on a molecule is removed and the molecule loses activity, what does this indicate about the group?
What is the primary function of a 'privileged scaffold'?
What is the primary function of a 'privileged scaffold'?
What is the purpose of the core scaffold achieving a specific 'fold' in three dimensions?
What is the purpose of the core scaffold achieving a specific 'fold' in three dimensions?
What does pharmacodynamics primarily focus on?
What does pharmacodynamics primarily focus on?
Which of the following is NOT a common drug target?
Which of the following is NOT a common drug target?
What is the primary focus of pharmacokinetics?
What is the primary focus of pharmacokinetics?
Which process is involved in pharmacokinetics?
Which process is involved in pharmacokinetics?
What is the ultimate goal of understanding both pharmacodynamics and pharmacokinetics?
What is the ultimate goal of understanding both pharmacodynamics and pharmacokinetics?
Which of the following is an example of a desired outcome of rational drug use?
Which of the following is an example of a desired outcome of rational drug use?
What is a potential side effect of antihypertensive drugs?
What is a potential side effect of antihypertensive drugs?
What is the focus of toxicology?
What is the focus of toxicology?
What is ED50?
What is ED50?
What database is used to monitor adverse events post-marketing?
What database is used to monitor adverse events post-marketing?
Increased lipophilicity of synthetic opioids leads to what?
Increased lipophilicity of synthetic opioids leads to what?
Which of the following factors influences drug absorption?
Which of the following factors influences drug absorption?
What is the Therapeutic Index?
What is the Therapeutic Index?
What does SAR stand for?
What does SAR stand for?
Which of the following is a pharmacokinetic process?
Which of the following is a pharmacokinetic process?
What factor can affect free drug concentration in the body?
What factor can affect free drug concentration in the body?
What patient characteristic may cause PD/PK differences?
What patient characteristic may cause PD/PK differences?
What does pharmacogenomics study?
What does pharmacogenomics study?
What is LD50 primarily used for?
What is LD50 primarily used for?
What is an ideal outcome of rational drug use?
What is an ideal outcome of rational drug use?
The mechanism of action (MOA) is important for understanding:
The mechanism of action (MOA) is important for understanding:
Which of the following describes pharmacodynamics?
Which of the following describes pharmacodynamics?
What can impact drug compartmentalization?
What can impact drug compartmentalization?
What is a key component of elimination?
What is a key component of elimination?
What does the Certain Safety Factor indicate about a drug?
What does the Certain Safety Factor indicate about a drug?
What is a ligand association constant?
What is a ligand association constant?
What is gauusian distribution?
What is gauusian distribution?
Which of the following pharmacokinetic factors change with age?
Which of the following pharmacokinetic factors change with age?
What is indicated by a high therapeutic index?
What is indicated by a high therapeutic index?
What is a ligand that activates a receptor and produces a biological response called?
What is a ligand that activates a receptor and produces a biological response called?
What term describes how tightly a ligand binds to a receptor?
What term describes how tightly a ligand binds to a receptor?
What is a stimulus response?
What is a stimulus response?
What does pharmacodynamics (PD) primarily describe?
What does pharmacodynamics (PD) primarily describe?
Which of the following antagonizes an agonist by competing for the same binding site?
Which of the following antagonizes an agonist by competing for the same binding site?
What does a lower EC50 value indicate about a drug?
What does a lower EC50 value indicate about a drug?
What does ADMET stand for in the context of pharmacokinetics?
What does ADMET stand for in the context of pharmacokinetics?
What is the maximal response of a drug referred to as?
What is the maximal response of a drug referred to as?
What does Bmax represent in receptor binding?
What does Bmax represent in receptor binding?
Why are GPCRs considered more 'druggable'?
Why are GPCRs considered more 'druggable'?
Which type of agonist stabilizes the active receptor state and elicits a maximal response?
Which type of agonist stabilizes the active receptor state and elicits a maximal response?
According to the content, what happens when all receptors are bound?
According to the content, what happens when all receptors are bound?
What does the Langmuir equation describe in the context of receptor theory?
What does the Langmuir equation describe in the context of receptor theory?
Before the discovery of opiate receptors, what was morphine known to be?
Before the discovery of opiate receptors, what was morphine known to be?
What term describes the signaling activity of a receptor in the absence of a ligand?
What term describes the signaling activity of a receptor in the absence of a ligand?
Which of the following is a key feature of allosteric modulators?
Which of the following is a key feature of allosteric modulators?
What enzyme does acetaminophen inhibit?
What enzyme does acetaminophen inhibit?
If a drug concentration equals Kd, what percentage of Emax is the response?
If a drug concentration equals Kd, what percentage of Emax is the response?
What is an additive effect in the context of multiple mechanisms of action?
What is an additive effect in the context of multiple mechanisms of action?
What happens to the dose-response curve if a drug binds less tightly to a receptor?
What happens to the dose-response curve if a drug binds less tightly to a receptor?
What effect does a Positive Allosteric Modulator (PAM) have on the dose-response curve?
What effect does a Positive Allosteric Modulator (PAM) have on the dose-response curve?
What does intrinsic activity measure?
What does intrinsic activity measure?
Which receptor class includes receptors that have a 7-transmembrane domain?
Which receptor class includes receptors that have a 7-transmembrane domain?
What is synergism in the context of drug action?
What is synergism in the context of drug action?
What is the primary goal of making drugs more selective?
What is the primary goal of making drugs more selective?
Which kind of receptor is generally intracellular and binds to lipids?
Which kind of receptor is generally intracellular and binds to lipids?
What is antagonism in the context of drug action?
What is antagonism in the context of drug action?
What is the alpha value of a full agonist?
What is the alpha value of a full agonist?
What type of ligand is buprenorphine?
What type of ligand is buprenorphine?
Which act prohibited misbranded drugs?
Which act prohibited misbranded drugs?
Older antipsychotics had poor selectivity and acted on dopamine and serotonin receptors, as well as:
Older antipsychotics had poor selectivity and acted on dopamine and serotonin receptors, as well as:
What characteristic defines a partial agonist?
What characteristic defines a partial agonist?
First generation antihistamines are?
First generation antihistamines are?
Which of the following is an example of irrational drug use?
Which of the following is an example of irrational drug use?
Newer antidepressants are more selective for serotonin transporters, which leads to:
Newer antidepressants are more selective for serotonin transporters, which leads to:
What is the alpha value of an antagonist?
What is the alpha value of an antagonist?
What is structural activity relationship?
What is structural activity relationship?
How do competitive antagonists affect the dose-response curve?
How do competitive antagonists affect the dose-response curve?
What is the term for the site on a receptor where a natural ligand binds?
What is the term for the site on a receptor where a natural ligand binds?
Which act required testing for both safety and effectiveness of drugs?
Which act required testing for both safety and effectiveness of drugs?
During which phase of the drug approval process are larger populations tested for rare adverse effects?
During which phase of the drug approval process are larger populations tested for rare adverse effects?
If 90% of receptors are blocked what protects the heart tissue from failing?
If 90% of receptors are blocked what protects the heart tissue from failing?
What effect do non-competitive antagonists have on Emax?
What effect do non-competitive antagonists have on Emax?
What is the specific molecular target?
What is the specific molecular target?
What is the alpha value of a full inverse agonist?
What is the alpha value of a full inverse agonist?
What does knowing a drug's MOA help us understand?
What does knowing a drug's MOA help us understand?
What was the initial intended benefit of COX-2 inhibitors?
What was the initial intended benefit of COX-2 inhibitors?
What happens to the MOA with repeated exposure?
What happens to the MOA with repeated exposure?
What action does a full agonist of the GABA receptor have?
What action does a full agonist of the GABA receptor have?
What role do pharmacists play in rational drug use?
What role do pharmacists play in rational drug use?
What is the effect of a full inverse agonist on the GABA receptor?
What is the effect of a full inverse agonist on the GABA receptor?
What is the study of the potential harmful effects of a drug called?
What is the study of the potential harmful effects of a drug called?
What is the alpha value of an antagonist at the GABA receptor?
What is the alpha value of an antagonist at the GABA receptor?
What does pharmacodynamics primarily study?
What does pharmacodynamics primarily study?
What is the focus of pharmacokinetics?
What is the focus of pharmacokinetics?
Which of the following is an advantage of fluorescence-based methods?
Which of the following is an advantage of fluorescence-based methods?
What is labeled with a fluorophore in biotin-avidin tagging?
What is labeled with a fluorophore in biotin-avidin tagging?
What led to Vioxx being withdrawn from the market?
What led to Vioxx being withdrawn from the market?
What effect does an inverse agonist have on receptor activity?
What effect does an inverse agonist have on receptor activity?
What does the statement 'Federal law prohibits dispensing without a prescription' indicate?
What does the statement 'Federal law prohibits dispensing without a prescription' indicate?
Which receptor state do antagonists bind to?
Which receptor state do antagonists bind to?
Which of the following is an advantage of label-free methods?
Which of the following is an advantage of label-free methods?
Who is responsible for educating patients on the proper usage of medication?
Who is responsible for educating patients on the proper usage of medication?
What is a key characteristic of ultra-rapid metabolizers concerning codeine?
What is a key characteristic of ultra-rapid metabolizers concerning codeine?
What is the function of an antagonist?
What is the function of an antagonist?
What is the primary concern with rapid metabolizers of S-warfarin?
What is the primary concern with rapid metabolizers of S-warfarin?
What is indicated with the addition of a Black Box warning after a drug has been approved?
What is indicated with the addition of a Black Box warning after a drug has been approved?
What is measured in isothermal titration calorimetry?
What is measured in isothermal titration calorimetry?
Which concept balances positive effects with toxicity?
Which concept balances positive effects with toxicity?
Which organization provides guidelines for the clinical use of drugs based on pharmacogenetics?
Which organization provides guidelines for the clinical use of drugs based on pharmacogenetics?
What kind of ions are ligand-gated ion channels selective for?
What kind of ions are ligand-gated ion channels selective for?
What does Bmax indicate?
What does Bmax indicate?
Variations in drug response can occur at which of the following levels?
Variations in drug response can occur at which of the following levels?
Where does GABA bind on GABA-A receptors?
Where does GABA bind on GABA-A receptors?
What does the slope of the binding curve reflect?
What does the slope of the binding curve reflect?
What is a key aspect of precision medicine?
What is a key aspect of precision medicine?
Benzodiazepines are examples of what?
Benzodiazepines are examples of what?
What is the study of variability in pharmacology due to genetic variations called?
What is the study of variability in pharmacology due to genetic variations called?
Which of the following describes pharmacokinetics (PK)?
Which of the following describes pharmacokinetics (PK)?
What does a Hill coefficient of 1 indicate?
What does a Hill coefficient of 1 indicate?
In the pharmacology model of drug discovery, what is a key question to address?
In the pharmacology model of drug discovery, what is a key question to address?
What can non-selective benzodiazepines cause?
What can non-selective benzodiazepines cause?
What does Bmax represent in receptor binding studies?
What does Bmax represent in receptor binding studies?
What do positive allosteric modulators (PAMs) generally do?
What do positive allosteric modulators (PAMs) generally do?
What is an adverse drug reaction (ADR)?
What is an adverse drug reaction (ADR)?
What range of alpha values corresponds to channel opening in the agonist direction?
What range of alpha values corresponds to channel opening in the agonist direction?
Where are drug targets typically localized?
Where are drug targets typically localized?
What distinguishes a partial agonist from a full agonist?
What distinguishes a partial agonist from a full agonist?
What is the first stage in activating a receptor?
What is the first stage in activating a receptor?
What is measured by IC50?
What is measured by IC50?
Which of the following is an example of a common side effect?
Which of the following is an example of a common side effect?
What is the primary function of cytochrome P450 (CYP) enzymes in drug metabolism?
What is the primary function of cytochrome P450 (CYP) enzymes in drug metabolism?
What is indicated by a lower Kd value?
What is indicated by a lower Kd value?
What do graphs of dose-response curves typically show on the Y-axis?
What do graphs of dose-response curves typically show on the Y-axis?
What does a lower IC50 value signify?
What does a lower IC50 value signify?
If two drugs have the same Emax and slope, what does this indicate about their mechanism of action?
If two drugs have the same Emax and slope, what does this indicate about their mechanism of action?
What does Ki represent?
What does Ki represent?
What must be known to determine if a drug is a full or partial agonist?
What must be known to determine if a drug is a full or partial agonist?
How do genetic variations in CYP enzymes affect drug response?
How do genetic variations in CYP enzymes affect drug response?
What arrangement defines the molecular structure of transmembrane receptors?
What arrangement defines the molecular structure of transmembrane receptors?
How is specific binding obtained?
How is specific binding obtained?
How does a partial agonist behave when combined with a full agonist?
How does a partial agonist behave when combined with a full agonist?
What is measured in radiolabeled drug-binding assays?
What is measured in radiolabeled drug-binding assays?
What is a potential consequence of being a poor metabolizer of a drug?
What is a potential consequence of being a poor metabolizer of a drug?
What can changes in a drug's structure affect?
What can changes in a drug's structure affect?
What is 'efficacy' in the context of receptors and drug response?
What is 'efficacy' in the context of receptors and drug response?
When generating a binding curve, what is plotted against the drug concentration?
When generating a binding curve, what is plotted against the drug concentration?
Which of the following is NOT a criterion for a receptor-mediated effect?
Which of the following is NOT a criterion for a receptor-mediated effect?
What does classical binding involve?
What does classical binding involve?
What can competition curves be used for in drug development?
What can competition curves be used for in drug development?
What is the normal, non-activated state of a receptor referred to as?
What is the normal, non-activated state of a receptor referred to as?
What is the role of Phase 2 metabolism?
What is the role of Phase 2 metabolism?
Which of the following is an example of an enzyme that acts as a drug target?
Which of the following is an example of an enzyme that acts as a drug target?
What happens to the equilibrium of receptor conformations when a ligand/drug is added?
What happens to the equilibrium of receptor conformations when a ligand/drug is added?
What does non-specific binding refer to?
What does non-specific binding refer to?
What is the formula for calculating drug residency time?
What is the formula for calculating drug residency time?
Which of the following is a characteristic of idiosyncratic reactions?
Which of the following is a characteristic of idiosyncratic reactions?
What does a longer drug residence time potentially affect?
What does a longer drug residence time potentially affect?
In a stimulus-response graph, what does a higher stimulus generally lead to?
In a stimulus-response graph, what does a higher stimulus generally lead to?
Through what mechanism do osmotically active drugs primarily act?
Through what mechanism do osmotically active drugs primarily act?
Why is a clear understanding of a drug's mechanism of action (MOA) important?
Why is a clear understanding of a drug's mechanism of action (MOA) important?
Which of the following is a limitation of using radiolabeled drug-binding assays?
Which of the following is a limitation of using radiolabeled drug-binding assays?
What is KD, the equilibrium constant, equal to?
What is KD, the equilibrium constant, equal to?
What is true about the Emax when spare receptors are present?
What is true about the Emax when spare receptors are present?
What is the definition of pharmacodynamics (PD)?
What is the definition of pharmacodynamics (PD)?
On a dose-response curve, what does a higher stimulus at less concentration typically indicate about an agonist?
On a dose-response curve, what does a higher stimulus at less concentration typically indicate about an agonist?
Which of these is an example of when 'tolerance' is considered a positive adaptation?
Which of these is an example of when 'tolerance' is considered a positive adaptation?
What happens when a ligand binds to a receptor in fluorescent labeling?
What happens when a ligand binds to a receptor in fluorescent labeling?
How is the EC50 affected in the presence of spare receptors compared to the KD?
How is the EC50 affected in the presence of spare receptors compared to the KD?
What aspect of drug response can be influenced by a patient's ethnicity?
What aspect of drug response can be influenced by a patient's ethnicity?
What does Surface Plasmon Resonance (SPR) measure?
What does Surface Plasmon Resonance (SPR) measure?
What happens when the therapeutic effect experiences sensitization?
What happens when the therapeutic effect experiences sensitization?
What happens to enzymatic activity in the presence of an inhibitor?
What happens to enzymatic activity in the presence of an inhibitor?
In a system with spare receptors, what is the initial effect of low concentrations of a non-competitive antagonist before Emax is affected?
In a system with spare receptors, what is the initial effect of low concentrations of a non-competitive antagonist before Emax is affected?
What kind of residency time does Dasatinib have?
What kind of residency time does Dasatinib have?
What is a medication error?
What is a medication error?
What is a benefit of spare receptors in a biological system?
What is a benefit of spare receptors in a biological system?
What kind of residency time do antiviral drugs tend to have?
What kind of residency time do antiviral drugs tend to have?
What percentage of occupancy of Beta-1 receptors by epinephrine is needed for Emax in the myocardium example?
What percentage of occupancy of Beta-1 receptors by epinephrine is needed for Emax in the myocardium example?
Which direction (positive or negative) corresponds to channel closing?
Which direction (positive or negative) corresponds to channel closing?
What kind of residency time does Verapamil, a calcium blocker, have?
What kind of residency time does Verapamil, a calcium blocker, have?
What needs do drugs like sleep aids typically require?
What needs do drugs like sleep aids typically require?
What is the residency time of the sleep drug Ambien?
What is the residency time of the sleep drug Ambien?
What is the approximate elimination rate of ambien?
What is the approximate elimination rate of ambien?
About how much occupancy is required for a sleep drug to be effective?
About how much occupancy is required for a sleep drug to be effective?
Which factor is an advantage of long-duration drugs?
Which factor is an advantage of long-duration drugs?
If concentration and affinity are unchanged, what happens when the off rate increases?
If concentration and affinity are unchanged, what happens when the off rate increases?
What does a high concentration of a long-duration drug with a long residency time ensure?
What does a high concentration of a long-duration drug with a long residency time ensure?
What is a direct consequence of longer residency times in tuberculosis drugs, as seen in animal studies?
What is a direct consequence of longer residency times in tuberculosis drugs, as seen in animal studies?
What does Emax represent on a dose-response curve?
What does Emax represent on a dose-response curve?
What might result from failing to measure kinetics over a relevant timeframe in structure-activity relationship (SAR) studies?
What might result from failing to measure kinetics over a relevant timeframe in structure-activity relationship (SAR) studies?
How does analyzing binding parameters and kinetics affect drug development?
How does analyzing binding parameters and kinetics affect drug development?
What does a steep slope in a dose-response curve indicate?
What does a steep slope in a dose-response curve indicate?
What does drug residency time primarily determine?
What does drug residency time primarily determine?
What can result from optimizing dosing regimens by understanding drug residency time?
What can result from optimizing dosing regimens by understanding drug residency time?
What advantage do log scales provide when analyzing dose-response curves?
What advantage do log scales provide when analyzing dose-response curves?
What do traditional binding assays sometimes fail to capture for compounds with long residency times?
What do traditional binding assays sometimes fail to capture for compounds with long residency times?
What does directly measuring the off rate and considering the half-life of a drug allow for?
What does directly measuring the off rate and considering the half-life of a drug allow for?
What is a key characteristic of a partial agonist?
What is a key characteristic of a partial agonist?
Drugs with similar mechanisms of action tend to exhibit which characteristic on dose-response curves?
Drugs with similar mechanisms of action tend to exhibit which characteristic on dose-response curves?
What does a normal slope in binding curves indicate?
What does a normal slope in binding curves indicate?
What does a shallow curve in binding affinity indicate?
What does a shallow curve in binding affinity indicate?
What can be inferred if two drugs have the same Emax?
What can be inferred if two drugs have the same Emax?
What kind of information is needed to determine if a drug is a partial agonist, versus having a different mechanism of action?
What kind of information is needed to determine if a drug is a partial agonist, versus having a different mechanism of action?
What do multiple slopes in a binding affinity indicate?
What do multiple slopes in a binding affinity indicate?
In the stimulus-response relationship, what does the drug-receptor interaction lead to?
In the stimulus-response relationship, what does the drug-receptor interaction lead to?
Ideally, to which receptor subtype should drugs selectively bind?
Ideally, to which receptor subtype should drugs selectively bind?
What is measured within the preclinical realm in regards to dose-response curves?
What is measured within the preclinical realm in regards to dose-response curves?
What do IC50 values correlate with?
What do IC50 values correlate with?
What does a lower IC50 value indicate?
What does a lower IC50 value indicate?
What does the KD value indicate?
What does the KD value indicate?
What does the pharmacodynamic (PD) category describe?
What does the pharmacodynamic (PD) category describe?
Which of the following is an example of a pharmacokinetic (PK) process?
Which of the following is an example of a pharmacokinetic (PK) process?
What should pharmacists understand to make informed decisions about patient care?
What should pharmacists understand to make informed decisions about patient care?
What does a positive correlation between binding and potency suggest?
What does a positive correlation between binding and potency suggest?
Which adrenergic receptor subtype is most strongly bound by Isoproterenol, according to content?
Which adrenergic receptor subtype is most strongly bound by Isoproterenol, according to content?
What does a direct correlation between bronchodilation and Beta Two binding indicate?
What does a direct correlation between bronchodilation and Beta Two binding indicate?
What is the likely outcome of a drug that selectively binds and activates beta two receptors?
What is the likely outcome of a drug that selectively binds and activates beta two receptors?
Where do drugs commonly originate from?
Where do drugs commonly originate from?
What are active compounds identified from high throughput screening called?
What are active compounds identified from high throughput screening called?
What skills overlap with SAR?
What skills overlap with SAR?
What does SAR provide for a pharmaceutical manufacturer?
What does SAR provide for a pharmaceutical manufacturer?
What does SAR help in understanding about drug-target interactions?
What does SAR help in understanding about drug-target interactions?
What are chemical groups that cause positive interactions with a target called?
What are chemical groups that cause positive interactions with a target called?
What can be determined by systematically truncating and replacing chemical groups?
What can be determined by systematically truncating and replacing chemical groups?
What is a pharmacophore?
What is a pharmacophore?
What might non-essential elements in a drug molecule be responsible for?
What might non-essential elements in a drug molecule be responsible for?
What does intrinsic efficacy describe regarding a drug?
What does intrinsic efficacy describe regarding a drug?
What characterizes a ligand with rapid kinetics?
What characterizes a ligand with rapid kinetics?
What happens to target occupancy as a ligand's concentration decreases?
What happens to target occupancy as a ligand's concentration decreases?
What is the main effect of slower receptor kinetics on drug action?
What is the main effect of slower receptor kinetics on drug action?
What is the impact of a faster ligand elimination rate on receptor occupancy?
What is the impact of a faster ligand elimination rate on receptor occupancy?
What adjustment is typically needed for a weak ligand to achieve the same target occupancy as a potent ligand?
What adjustment is typically needed for a weak ligand to achieve the same target occupancy as a potent ligand?
What is one of the primary aims of Structure-Activity Relationship (SAR) studies?
What is one of the primary aims of Structure-Activity Relationship (SAR) studies?
Why is time an important factor in drug action?
Why is time an important factor in drug action?
What does the Occupancy Theory primarily describe?
What does the Occupancy Theory primarily describe?
According to the Law of Mass Action, what is the relationship between receptor occupancy and response?
According to the Law of Mass Action, what is the relationship between receptor occupancy and response?
In the context of drug-receptor interactions, what does Kon represent?
In the context of drug-receptor interactions, what does Kon represent?
What does the dissociation constant (Kd) measure?
What does the dissociation constant (Kd) measure?
According to the Langmuir equation, what percentage of the maximal effect is observed when Kd is equal to the drug concentration [D]?
According to the Langmuir equation, what percentage of the maximal effect is observed when Kd is equal to the drug concentration [D]?
Which of the following parameters affects drug response?
Which of the following parameters affects drug response?
Which of the following contributes to patient variability in drug response?
Which of the following contributes to patient variability in drug response?
Flashcards
Rational Drug Use
Rational Drug Use
Medications used with a clear therapeutic goal, ensuring patients receive appropriate, effective, and affordable treatment.
Key factors for rational drug use
Key factors for rational drug use
Using the right medicine, at the right dose, in the right form, through the right route, at the right frequency, for the right duration.
Curing a Disease
Curing a Disease
Understanding what went wrong in the body, how to fix it (block or activate), and the signaling pathways involved.
How Antibiotics Work
How Antibiotics Work
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Replacement Therapy
Replacement Therapy
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Most Drugs Act By
Most Drugs Act By
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FDA-Approved Novel Drugs
FDA-Approved Novel Drugs
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Number of Prescription Drugs Available
Number of Prescription Drugs Available
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Pharmacology
Pharmacology
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Drug Potency
Drug Potency
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Drug Efficacy
Drug Efficacy
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Drug Duration of Action
Drug Duration of Action
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Pharmacogenomics
Pharmacogenomics
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Pharmacokinetics
Pharmacokinetics
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1906 Pure Food and Drug Act
1906 Pure Food and Drug Act
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1938 Food, Drug & Cosmetic Act
1938 Food, Drug & Cosmetic Act
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1951 Durham-Humphrey Amendment
1951 Durham-Humphrey Amendment
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1962 Kefauver-Harris Amendment
1962 Kefauver-Harris Amendment
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Black Box Warning
Black Box Warning
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Risk Evaluation Mitigation Strategies (REMS)
Risk Evaluation Mitigation Strategies (REMS)
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Pharmacodynamics
Pharmacodynamics
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Therapeutic Index
Therapeutic Index
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Drug Targets
Drug Targets
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Benefit vs. Risk
Benefit vs. Risk
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Therapeutic Benefit
Therapeutic Benefit
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Side Effects
Side Effects
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Quantifying Benefit-to-Risk
Quantifying Benefit-to-Risk
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Toxicology
Toxicology
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Opioid Toxicology
Opioid Toxicology
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Drug Selectivity
Drug Selectivity
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Structure-Activity Relationship (SAR)
Structure-Activity Relationship (SAR)
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Free Drug Concentration
Free Drug Concentration
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Mechanism of Action (MOA)
Mechanism of Action (MOA)
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Core Scaffold Definition
Core Scaffold Definition
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Core Scaffold Structure
Core Scaffold Structure
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Core Scaffold Function
Core Scaffold Function
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Shape Matters
Shape Matters
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Privileged Scaffold
Privileged Scaffold
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Ultra-Rapid Metabolizers (Codeine)
Ultra-Rapid Metabolizers (Codeine)
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Poor Metabolizers (Codeine)
Poor Metabolizers (Codeine)
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Rapid Metabolizers (S-Warfarin)
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CPIC Guidelines
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Ligand Stimulus-Response
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Receptor Basal State
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Activated Receptor Conformation
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Agonist
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Pharmacodynamic Variation
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Personalized medicine
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Pharmacodynamics (PD)
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Pharmacokinetics (PK)
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Pharmacophore
Pharmacophore
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Structural Activity Relationships
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Receptors
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Benefit-Risk Balance (Drugs)
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Kinases
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Proteases
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Adverse Drug Event (ADE)
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Glycoproteins
Glycoproteins
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Adverse Drug Reaction (ADR)
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GPCRs (G protein-coupled receptors)
GPCRs (G protein-coupled receptors)
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Additive effect
Additive effect
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Allergic Reaction
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Idiosyncratic Reaction
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Synergism
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Antagonism
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Tolerance
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Multiple Targets
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Genetic Polymorphisms
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Dynamic MOA
Dynamic MOA
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Cytochrome P450 (CYP) Enzymes
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Phase 2 Metabolism
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Poor Metabolizers
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Rapid Metabolizers
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Prodrug
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Affinity
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Orthosteric Binding Site
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Competitive Antagonist
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Effector/G-protein
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EC50
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Emax
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Partial Agonist
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Allosteric Modulators
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Positive Allosteric Modulator (PAM)
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Negative Allosteric Modulator (NAM)
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Maximal Efficacy (Emax)
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Potency
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Law of Mass Action
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Similar Mechanisms of Action
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Slope (Dose-Response)
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Log Scale
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Receptor Occupancy
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Kd Value
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Pharmacogenomic differences
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Intrinsic Efficacy
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Number of Receptors
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Receptor Kinetics
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Ligand concentration effect on receptor occupancy
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Slow Receptor Kinetics
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Ligand Elimination Rate
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Weaker Ligand
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Patient Variability
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Occupancy Theory
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Law of Mass Action Assumptions
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Kon
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Koff
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Dissociation Constant (Kd)
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Langmuir Equation
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Ligand-Gated Ion Channels
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Benzodiazepines
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Alpha Subunit Specificity
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Binding Curves
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Total Binding
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Non-Specific Binding
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Specific Binding
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Bmax (Maximum Binding)
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Kd (Dissociation Constant)
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Radiolabeled Drug-Binding
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Bmax Significance
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Specific Binding Importance
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Kd and 50% Response
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Koff and Potency
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Intrinsic Activity
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Full Agonist
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Non-Competitive Antagonists
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Full Agonists (Alpha Value)
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Partial Agonists (Alpha Value)
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Inverse Agonists (Alpha Value)
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Pharmacogenomic Variability
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ADME Profiling
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Pharmacodynamic Variability
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ED50 (Effective Dose 50%)
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TD50 (Toxic Dose 50%)
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LD50 (Lethal Dose 50%)
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Certain Safety Factor
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Risk-to-Benefit Analysis
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Stimulus Response
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Pharmacokinetic (PK) Parameters
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Pharmacodynamic (PD) Parameters
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Single Nucleotide Polymorphism (SNP)
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Fluorescence-Based Methods
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Biotin-Avidin Tagging
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Homogeneous Time-Resolved (FRET)
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Label-Free Methods
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Surface Plasmon Resonance (SPR)
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Isothermal Titration Calorimetry
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Nuclear Magnetic Resonance (NMR)
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Mass Spectrometry
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Slope of Binding Curve
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Hill Coefficient
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Competition-Binding Curves
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IC50 (Inhibitory Concentration 50%)
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Alpha Values
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Comparing Agonists
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Same Emax & Slope
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Partial Agonist + Full Agonist
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Receptor-Mediated Effect
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Common Receptor Types
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Enzymes as Drug Targets
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Drugs NOT Acting via Receptors
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Spare Receptors
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Spare Receptors: EC50 vs KD
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Clinical Importance of Spare Receptors
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Long Duration Drugs
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Advantages of Long Duration Drugs
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Drug Residency Time
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Drug Residency Time Importance
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Limitations of Traditional Binding Assays
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Assessing Drug Kinetics
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Hill Coefficient of One
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Shallow Binding Curve
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Multiple Slopes in Binding Curves
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Subtype-Selective Drugs
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IC50 Value
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Lower IC50 Value
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Drug Selectivity for Receptor Subtypes
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Purpose of Competition Curves
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Tables of IC50 Values
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Residency Time Calculation
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K off Rate
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K on Rate
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KD (Equilibrium Constant)
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Fluorescent Labeling
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Saturation and Washout
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Residency Time & Efficacy
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Enzyme Inhibition
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Residency Time Varies
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Concentration & Occupancy
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Short-Acting Drugs
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PKPD Modeling
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SAR Definition
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High Throughput Screening
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SAR in Hit Optimization
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Iterative Approach of SAR
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Pharmacophore Definition
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Minimum Structural Features
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Balancing Drug Effects
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Maximal Bronchodilation
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Direct Correlation in SAR
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No Correlation in SAR
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Non-Essential Elements in SAR
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Plotting Activity Values
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Therapeutic Window
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SAR and Intellectual Property
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Molecular Forces of Interaction
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Study Notes
- Rational drug use means using medications with a therapeutic goal.
- Patients should receive appropriate medications approved by the FDA, at the right dose and duration, and at the lowest cost.
- Key factors involve the right indication, dose, dosage form, route, frequency, duration, information, and follow-up.
How Drugs Work
- Curing a disease requires understanding its mechanism, including what went wrong, how to fix it, and whether to block or activate a receptor or system.
- Complete understanding of pathophysiology is often lacking.
- Antibiotics can cure illnesses but can also kill good bacteria and lead to antibiotic resistance.
- Replacement therapy is effective for conditions like insulin deficiency.
- Most drugs treat symptoms, not the cause, but the goal is to develop drugs that cure diseases by targeting underlying mechanisms.
FDA Drug Approvals and Statistics
- Novel drugs approved by the FDA in 2022 numbered 37, which is a decrease from about 100 in 2021,
- Most approvals were for new formulations or modified labels, with only about five new indications.
- Novel drugs approved in 2022 targeted COVID-19, HIV, smallpox, influenza, CNS disorders, heart, blood, kidney, endocrine, diabetes, autoimmune disorders, and cancers.
- Rare diseases accounted for 54% of novel drugs in 2022.
- Over 10,000 prescription drugs are available.
- Over 6.7 billion prescriptions were ordered in 2022 which is a 3.6% increase over 2021.
- Prescription rates have been increasing about 1% per year since 2016.
- About 81% of physician visits result in a prescription.
- People over 65 account for over 34% of prescriptions in the U.S., while comprising 16.3% of the population.
- People over 65, 36% take five or more prescriptions, compared to 20% of people aged 45 to 64, potentially causing drug-drug interactions.
- The FDA receives over 100,000 reports of medical errors per year.
- medication errors harm an estimated 1.5 million people per year.
Risk vs. Benefit
- Even a 1% risk of adverse effects is considered high.
- Key concepts include drug potency, efficacy, duration of action, pharmacogenomics, and pharmacokinetic parameters.
- The goal is to increase benefits and decrease adverse effects by making drugs more selective for certain pathways and receptors.
Historical Perspective
- Historically, "medicine men" provided agents that might make people feel better.
- The Industrial Revolution led to bottled herbal remedies, often containing alcohol.
- It became necessary to ensure that drugs were marketed as safe and rational.
Irrational Drug Use
- Includes misuse, overuse, polypharmacy, drug-drug adverse effects, ineffective treatment, unsafe self-medication, overuse of antibiotics, and wrong medication for a given indication.
- Negative health outcomes, increased costs, and lower patient confidence are results of inappropriate medicine use.
Legislation for Rational Drug Use
- Federal Pure Food and Drug Act (Wiley Act) instituted in 1906.
- The Wiley Act banned misbranded or adulterated foods, drinks, and drugs.
- The Wiley Act also prohibited false or misleading label claims.
- The Wiley Act required correct labels with inspections and registration of addicting substances.
- Federal Food, Drug, and Cosmetic Act instituted in 1938.
- The Food, Drug and Cosmetic Act demanded safety testing, accurate and complete labels, and factory inspections.
- Durham-Humphrey Amendment instituted in 1951.
- The Durham-Humphrey Amendment seperated more dangerous drugs from less dangerous ones.
- The Durham-Humphrey Amendment required injectables to have the statement "Federal law prohibits dispensing without a prescription" on labels.
- The Durham-Humphrey Amendment regulated narcotics, hypnotics, and habit-forming drugs, required separate prescriptions for over-the-counter drugs and limited drugs to investigational use
- Kefauver-Harris Amendment instituted in 1962.
- The Kefauver-Harris Amendment required testing for safety and effectiveness for all new drugs and those approved between 1938 and 1962.
New Drug Approval Process
- Includes phases one, two, three, and four
- Phases one through three tests are conducted on a relatively small number of people.
- Phase four is where larger populations are tested.
- Rare adverse effects might now be seen until phase four or after a drug is widely used.
- Black box warnings may be added to drugs after they are approved and distributed.
- Efficacy may outweigh the side effects, depending on the condition being treated.
Example: COX-2 Inhibitors
- COX-2 inhibitors (e.g., Vioxx, Celebrex, Bextra) developed as analgesics and anti-inflammatory agents.
- COX-2 inhibitors were designed to be more selective for COX-2 over COX-1.
- The goal was to reduce stomach ulcers and bleeding events.
- Arachidonic acid breaks down into prostaglandins, prostacyclins, and thromboxane
- Prostaglandins, prostacyclins, and thromboxane are signaling molecules involved in pain, inflammation, stomach function, kidney function, and blood clotting.
- COX-1 enzymes are involved in all these processes.
- COX-2 enzymes affect only inducible prostaglandin synthesis, not thromboxane.
- Vioxx rapidly approved in 1999. Initially, considered a significant benefit due to avoiding issues with blood clots and stomach issues.
- However, larger studies revealed that Vioxx increased the risk of myocardial infarction
- It was discovered that the inhibition of prostacyclin contributed to the increased risk of heart attacks.
- Studies of high doses of Vioxx (18 months) and reoccurring colon polyps doubled blood clots.
- Vioxx and Bextra were withdrawn from the market due to these risks.
- A black box warning was added because Celebrex was used for arthritic pain, and the risk to benefit was deemed acceptable in patients without cardiac issues.
Pharmacist's Role in Rational Drug Use
- Pharmacists help ensure the rational use of drugs, correct, and avoid mistakes.
- Risk Evaluation Mitigation Strategies (REMS) are used for better training and certification for physicians and pharmacists.
- It is essential to be aware of the risks and benefits of drugs.
- Education is essential in ensuring the right drug, for the right indication, for the right duration.
- Pharmacogenetic profiling may be beneficial but requires understanding drug mechanisms of action.
- The therapeutic index is the balance of positive effects versus toxicity.
- A good therapeutic index requires understanding the target, mechanism, and pathophysiology of disease.
- Pharmacists educate patients on usage and side effects, conduct medication reconciliations, and counsel patients on diseases and medications.
- Pharmacists must involve patients in treatment decisions to reduce risks of errors and adverse events.
What is Pharmacology?
- Pharmacology is the study of a pharmakon, which can be a poison or a cure.
- A poison causes more harm than benefit
- A cure (or drug in the modern context) should cause more benefit than harm.
- Pharmacology is an interdisciplinary science that studies the fate (pharmacokinetics) and action (pharmacodynamics) of a drug in relation to its therapeutic value.
Key Terms
- Pharmacodynamics: What a drug does to the body, its mechanism of action and how a drug causes benefit.
- Pharmacokinetics: What the body does to the drug as it moves through the body, important for deciding the dosage and formulation of a drug.
- Toxicology: The study of the potential harmful effects of a drug, used to estimate the risk associated with drug use.
Pharmacodynamics in Detail
- Pharmacodynamics focuses on the therapeutic benefit of using a drug.
- To understand the benefit, it's important to study the mechanism of action, molecular, or biomolecular target of the drug, and what the drug interacts with in the body.
- Common drug targets include receptors, ion channels, enzymes, and transcription factors.
- Location of the target or target tissue is important.
- Opiates target the CNS for pain control, but may also target the GI, causing side effects like constipation.
- Pharmacodynamics is crucial to maximize benefits and reduce risks.
Pharmacokinetics in Detail
- Pharmacokinetics studies the fate of the drug in the body.
- The processes include absorption, distribution, metabolism, and excretion.
- Pharmacokinetic processes influence the drug's action (pharmacodynamics).
Benefit vs. Risk
- Knowledge of both pharmacodynamics and pharmacokinetics helps in determining if a drug has more benefit than risk or toxicity.
- The goal is to achieve a balance for safe and effective or rational drug use.
Benefits of Rational Drug Use
- Examples of desired health outcomes: Antihypertensives lower blood pressure, birth control pills prevent conception, antibiotics kill infectious organisms, and antipsychotics decrease delusions.
Side Effects
- Even intended use can lead to side effects.
- Examples: Antihypertensives cause drowsiness or impotence; birth control pills: headaches, depression, blood clots; antibiotics: diarrhea, yeast infections, resistance; antipsychotics: movement disorders, tardive dyskinesia, weight gain.
Maximizing Benefit and Minimizing Risk
- Requires knowledge of pharmacodynamic characteristics, target presence and validity, pharmacokinetic characteristics, metabolites produced, patient history, other medications, and patient-to-patient variability.
Quantifying Benefit-to-Risk
- Parameters such as therapeutic index and safety factors are used.
Toxicology in Detail
- Toxicology involves the study of risk of harm from drug use.
- Adverse effects can be caused by incorrect exposure or use.
- Toxicology focuses on prescription drugs and rational use.
- Toxicology studies are done during drug development before FDA approval and marketing.
- Post-marketing surveillance involves monitoring adverse events and reporting them to the FAERS database.
How PD Influences Toxicology
- Opioids have increased potency at opioid receptors.
- Increased lipophilicity in Opioids leads to good CNS exposure.
- Increased potency and availability lead to increased side effects under prescription and overdose risk.
- There was a 100% increase in death rate from synthetic opioids between 2015 and 2016.
How PK Influences Toxicology
- Potent and lipophilic opioids pose an environmental risk to first responders.
- Exposure can occur through inhalation and mucus membranes.
- Toxicology studies how this affects drug use overall.
- Highly potent drugs can be toxic at very low concentrations.
- Every drug can be toxic at high enough concentrations.
- Drugs are tested at the highest possible doses during development.
Controlling Benefit-to-Risk Ratio
- PD Factors: A drug may have multiple targets or sites of action; the goal is to identify the target that leads to therapeutic value.
- Off-target effects should be minimized by making the drug more selective and understanding the mechanism of action.
- Benefit and risk can be increased by Changing drug structure through chemistry to to increase potency, reduces risk and increases benefit, decrease dose
- Understanding drug-receptor interaction (binding and potency) is also important,
- Functional group and SAR (structure-activity relationship) knowledge is necessary.
PK Factors
- The free drug concentration is available for action in the body.
- Low absorption can reduce free drug concentration.
- Changes to the drug structure may be necessary to increase absorption.
- Structure changes may alter drug distribution, which may increase both the benefit and risk.
- Half-life and metabolism rates can also affect free drug concentrations.
- Location-specific PK studies can help control these issues.
- Metabolites can increase the risk of the original drug.
Patient Variability
- PK and PD can vary based on the drug and also the patient.
- Pharmacogenomics studies how genes affect a person's response to a drug, impacting PD, PK, and toxicology.
- CYP enzymes metabolize the active drug to an inactive form.
- Normal metabolizers do not have a buildup of the drug.
- Poor metabolizers may have a buildup of the active drug, leading to increased bleeding risk.
- Pharmacogenomics can suggest different dosing or a different drug for poor metabolizers.
- Patient variability in genes and disease states can alter PD and PK, ultimately affecting the benefit-to-risk ratio.
Summary
- Pharmacodynamics, pharmacokinetics, and toxicology all have a bearing on the benefit to risk ratio in drug use.
- Outcomes can vary such as a drug not being rationally used because the patient dos not benefit or drugs being dangerous because because the patient is harmed without benefit.
- Rational drug use is achieved by controlling PK, PD, and toxicology to balance benefit versus risks.
Understanding a drug's MOA
- Differentiation between beneficial and side effects requires you to underrstand the drug's mechanism of action
- Pharmacodynamics (PD) is what the drug does to the body, or the MOA
- Pharmacokinetics (PK) is what the body does to the drug
Importance of Knowing the Mechanism of Action
- Knowing a drug's MOA is crucial in pharmacology.
- Helps one understandhow and where the drug acts.
- Aids in finding, identifying the key structural components of the drug, known as the pharmacophore,
- Understanding MOA helps to increase the benefit and decrease the toxicity of a drug
- helps to identify a dose for a drug that is selective against one target over many targets it may interact with
- find a window where a drug may have more benefit than harm.
Common Drug Targets
- Ion channels
- Receptors (especially GPCRs)
- Transcription factors
- Enzymes (kinases and proteases)
- Nucleic acids
- Glycoproteins expressed on the cell surface, which are important for cell communication.
- GPCRs are considered more "druggable" because they allow for more selective targeting with fewer side effects.
Limitations to Understanding the Mechanism of Action
- MOAs are not always easy to understand and can be limited by understanding, technology and target knowledge.
- A drug may act with multiple targets or responses, and MOA can be dynamic exposure from the drug
Limitations Explained
- Limited by our understanding and technology
- Morphine was known as analgesic but specific target was unknown until 1974 when discovering opiate receptors
- Activating opiate receptors leads to downstream signaling, causing both benefits and side effects.
- More recently Opiates that block parts of this downstream signaling are being developed to reduce side effects.
- Acetaminophen before 1970, was thought to block bradykinin, but this was only true at very high doses.
- Acetaminophen after 1970, was found to inhibit the cyclooxygenase enzyme (COX) which inhibits production of anti-inflammatory molecules.
- Acetaminophen selectively inhibits COX-1b, reducing the risk of side effects such as GI ulcers and bleeding associated with aspirin.
- Recent research shows that acetaminophen also interacts with cannabinoid and TRPV1 receptors, which are important for pain.
- A drug may have more than one mechanism of action
- A drug may bind to multiple receptors or interact with multiple mechanisms.
- Side effects can also be derived from multiple interactions.
- It is important to identify all the targets for a drug to correlate benefit or side effects to each individual target.
- Research is focused on how to block the side effects by targeting specific downstream signaling from interaction with the same receptor
- Multiple modes of action can combine in different ways:
- Additive effect: The combined effect is the sum of the individual effects.
- Synergism: The combined effect is greater than the sum of the individual effects.
- Antagonism: The combined effect is less than the sum of the individual effects.
- Multiple modes of action can result in additive, synergistic, or antagonistic effects
- A drug may have a better benefit versus toxicity profile by blocking one target that causes side effects while activating another target that leads to benefit.
Example: Older Antipsychotics
- Older antipsychotics block dopamine and serotonin receptors.
- These drugs had poor selectivity and acted on other receptors, leading to increased side effects.
- However, off-target actions at cholinergic receptors led to a reduction in motor side effects.
Example: Newer Antidepressants
- Newer antidepressants are serotonin reuptake inhibitors that increase the amount of serotonin at the junction between two neurons.
- Older drugs in this category had many side effects and higher overdose risk.
- Newer drugs are more selective, with decreased risk of side effects.
- By being more selective, they narrow the mode of action, increasing the benefit reducing risk.
Benefit versus Risk Knowledge
- Knowledge of all modes of action is necessary to completely understand benefit versus risk.
- The MOA may change over time with repeated exposure since the the body reacts and may reset.
- Example: Opioids
- initial receptor activation occurs within hours, but tolerance develops after a week
- Example: Antidepressants
- the re-uptake of serotonin is blocked within hours but therapeutic benefits can take weeks
- The benefit-risk balance is not static
Sensitization
- Sensitization of the therapeutic effect is good because it allows for the use of smaller doses.
- Sensitization of side effects is not desirable, such as tardive dyskinesia.
- Tolerance to side effects over time, such as sedation, is useful if allowing the drug to deliver the desired benefits.
Conclusion
- A clear MOA is important for drug development
Pharmacogenomics
- Pharmacogenomics is the study of variability in pharmacology due to genetic variations.
- Pharmacogenomics examines how genetic variability affects a person's response to drugs
- Pharmacogenomics includes how pharmacokinetics (PK) and pharmacodynamics (PD) are affected by genomic variability.
Adverse Drug Events (ADEs)
- Definition of harm resulting from medical drug use.
- ADEs relate to drug use and include medication errors and adverse drug reaction.
- ADEs vary from patient to patient
Side Effects
Specific ADRs that are common and sometimes known
Genetic Variability and Disease
- Variations need to be taken into account when considering medications.
- Effects on treatment, efficacy, dosage, and effects
Term: Pharmacokinetics (PK)
-ADMEs that vary from patient to patient because they are carried out by enzymes that are related to genes.
- Genetic variability can affect receptors, ion channels, the immune system, and enzymes.
Pharmacogenomics aids in decision-making
- genetic variations alter enzymes, affect metabolites, and interactions
Metabolism: Phase 1
- Primarily though cytochrome P450 (CYP) enzymes doing oxidation, reduction, and hydrolysis
- converts to metabolizers, and activates, or deactivated the drugs
- highest liver concentration
- patients variability with classifications Low risk of drug-drug interactions with phase 2
Drug activity
- Patients may be rapid, normal, intermediate, and poor metabolizers -poor is slow, leads to higher drug level, side effects -rapid metabolizes rapidly, leading to effects CYP2D6 is an example
- multiple enzymes and metabolic pathways
- difficult to study
Clinical Guidelines
- CPIC provides guidelines for clinical drug use Include drugs to improve therapy regimens
Pharmacogenomics and Pharmacodynamics
- receptor variation
- drug binding
- post receptor variation
- conccurent drugs and interactions precision Precision: is an emerging approach utilizing genes, lifestyle, and environment Pharmacists will see it more
Drug Stimulus-Response and Dose-Response Curves
- The activity in the systems
- What is the drug, and how will it behave
- chemical communicate inside and outside
- Variability arises from isoforms
How do drug-membrane receptors function
Basal state: normal, non-activated state. Equilibrium state Conformation changes Graphs will vary stimulus with concentration Dose- Response variation with concentration
Dose-Response characteristics
- Emax -The potency and largest response Clinical Usefulness depends on the efficacy and indications Need high or less
-slope varies individual response to dose Mass action
Slopes
Steep slope indicates positive cooperativity or spare receptors Shallow slope indicates negative cooperativity or multiple receptors. Log scales will make it easier Potency matters for side effects Partial Agonists: Don't max like a full Extract values from the curve
Different effects and actions
Different maximal efficacies Inhibitors are lower max Partial will fully activate There is also the simulus and dependancy and relationship
Dose-Response Curves
- Graded responses in cells, tissues, and animals are what is recorded for a dose-response
Different Responses measured per tissue in the Preclinical realm:
- Measuring and quantifying responses
- Different concentrations result in different responses
- Muscle Tissue: Measuring force and changes with drug addition -Cells: Measuring cell viability and death with anti-cancer drugs
Patient Response is slightly different:
- Patient Response: More commonly measured an all-or-none response due to thresholds.
- Example: Pain scale (0-10) where a level of 7 might be the threshold for a response.
- Values obtained are slightly different from EC50 values
Terms:
- Bmax: Maximal binding.
- KD Value: Half-maximal binding, indicating affinity for the target. Affinity vs. Potency:
- Occupancy measures target affinity
- Response measures potency.
- Patient Variation: Patients respond differently to the same dose of a drug,
Outcomes may be drug efficacy
- Beneficial and Non-Toxic for benefit .
- Toxic and Non-Beneficial is undesirable . Larger Group Exhibit Effects in some cases
PK/PD Responses
These may include:
-
Pharmacokinetic (PK) for What the body does to the drug.
- Absorption, excretion, metabolism.
-
Pharmacodynamic (PD) .
- What the drug acts and does. Drug induces change.
-
Pharmacogenomic . contributes to variability in genetic variability
Pharmacokinetic
ADME Profiling: Absorption, Distribution, Metabolism, Elimination.
- Absorption
- influences: Stomach contents (full vs. empty), skin texture (topical).
- Metabolism
- influences include Hepatic functions, Age, enzyme variations.
Pharmacodynamic
What the drug does by binding. Factors: Receptor Number: Signal Transduction: Different signaling pathways. . patient factors and variability
- Body factors and body compostitions that influence drug and release.
- Disease state and also genetics
Quantal Response Curves
Number of people responding with dose and threshold
Factors to measuring response curves
threshold Complete response threshold
Thresholds affect the curve
ED50 and LD50 in preclinical situations for effect and lethality -ED50 as effective vs -TD50 as toxic
Therapeutic Safety Factors
- Safe
- Ratio of effect vs effects Non-Compliance should be factored
Risk analysis. Consider:
what specifics about your patient, then magnify those effects?
- What do you know about your patient that magnifies the bad effects? .
- As a pharmacist, what other factors can you really control and magnify?
PK-PD Simulations Key Concept Include
- dose-response relationships and parameters. Receptor kinetics pharmacokinetics SNP or single-nucleotide polymorphism
Kinetic and Pharmacodynamic simulations
how fast as a constant, the ligand concentration, the target is, association between receptor over action vs toxicity
The simulations examples
Rapid kinetics drugs that quickly dissociate and a few effects
- Extended action drugs will vary and show higher efficacy
SAR helps make better and potent drugs. With time key
Receptor Theory
Involves drug concentrations moleculars
Binding
One drug binds or vice versa Occupancy half response Reversible and lock and key fit Negligible effects from drugs. Terms exist and include free and drug and complexes Complex to stimulus with activity Reverse factors must be considered too Drug interactions are used for affinity
Binding factors
-Langmuir, kd and relating of a drug B max is needed and reach binding. Factors and relationships needed to determine the value.
Drugs don't react always but are equal different populations happen. Use modify with alpha Alpha values will vary action with receptor Full -1 Full agonists will happen and alpha
Antagonists.
Partial do not produce as much but at the same target If the slope, then it's not the action of a full drug .
- Antagonists have no response blocking ability to all agents
Types of antagonistics
-binding
decrease to potency or not
Effect Inverse of all actions, values 0 to -1 Bind at interface and modulators and is more safer
Receptor class
G proteins Coupled proteins Nuclear and linked Neurotransmitters Alpha values Effect and bind Selectivity Isoforms
Receptor theory two
There are alpha and antagonistis Use for Gaba Or opposite with alertness EC and EM
Drug similarities need
Receptor occupancy is need Some partials can do different Excessive responses are due
Requirements for effective receptor
-stereo Selectivity to target ratio Saturability at lower levels
Receptor types
-channels(GABA), G-protein and couples -nuclelic acids -glycoproteins Some don't go though receptors. Membrane, osmotic, ph and more Excess Dose has changed and it impacts
Theory section 3
Component and ligand Stimulated with antagonist. More efficient Potency effects. Activity does or not in system
Full vs parital
Stabilizes different states. Is opposite. Modulates the effect. Selectivity The main receptors G protein Cases of partial and modifiers Withdraws Binds the receptor Stimulates activity Reduce side effects
Actions
Inverse
Different responses
Alpha and other sub units
- Selective to bind to forms More selectivity if needed.
Key things.
Terms and action Compared againsts
Key is drug conc
Binding affinity Receptor target response Specificity is direct or indirect
- Specific bindingCharacteristics: for specific binding, the binding curve should have a normal slope, indicating that the law of mass action is followed. A normal slope is characterized by an 80% response within a 100-fold window of drug concentration.
Studied methods
-
Binding drug with radiation -less safe and resources
-
Based methods: Fluorescence -Less benign than radiolabeled .
Biotin and Avidin -Strong interaction . Fluorophore are required
-
Label Methods no needed -requires specialized equipment surface titration magentic and more
Binding slope
- Reflects drug specific binding . Indicates cooperation of binding molecules and increased or decreased affinity molecules binding Changes in structure and shape change KD and KI
Binding in competition
- Competition curves can confirm if a compound comes from works at the intended receptor if is no a molecule to target it Is the labeled binding is displaced. If binding is displaced
- The concentration of the unlabeled drug required to inhibit 50% of the labeled ligand binding the IC50 values. Ki is calculated from the IC50 values
Applications of Competition Curves
- Verifying new molecule targets
- Assesses for selectivity bind
- Compare the drugs compound with affinity
- Guide efforts
Residencial Time to calculate
Time of the concentration Equilibrium by calculation Calculates with KD or other elements Averaged drug with more time affecting efficacy. Experimental: fluo and dilution Measure of activity Clinically helps and tailors. Key parameters
Residency Key parameters.
Key: DRUG concentration occupancy actions
Drug Actions
sleep is about 5 min and long may be required. Balance Drugs that take longer are protected, therefore has more In vivo helps. Kinetic allow assessment for effectiveness and safety
Review on effectiveness.
More effects depends drug types Assess effectiveness based on different regimens Binding can lead to better results too
Relationships structure
Slope can result receptors from drug molecule If shallow results averaged in the population Curve has several slope
- The affinity of is is dependent with
Drugs must bind the following to determine potency
-benefit and also harm Find a great balance High effective with high concentrations Subtype for benefit best effects Reality by tissue and disease Drugs by table for easy results
Affinity drug decisions
Benefits and potentcy to drug effects Spikes results different by affinity. Direct or not correlaton Beta can result from all of them Drugs give better results
Activity and Effects Relationship
Helps reduce drug harms effects if binded -Window can allow better care overall
Activity Structure
The molecule is connected with drugs
- Helps with origin
Importance from the discovery
Hits as origin molecule Uses SAR to prioritize Data added help in collection Analizes structure and data and helps with chemistry. All aspects
Terms is for activity with drugs
Molecular interactions must work
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Description
Explore rational drug use, its key aspects, and the importance of disease mechanism understanding. Discusses drug limitations, FDA approvals in 2022, and the impact of polypharmacy. Focuses on molecule core scaffolds and pharmacodynamics.
