Quiz 1- Lectures 1,2,3 Flashcards
(49 cards)
1
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Magic bullet hypothesis
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- A compound that will selectively target a disease
2
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Pharmacology
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The study of drugs
3
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Pharmacodynamics
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What the drug does to the body; the molecular mechanism of action of the drug
4
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Pharmacokinetics
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What the body does to the drug’ deals with concentration, metabolism, elimination, etc
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Phamacogenetics
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Genetic differences resulting in different responses to drugs
6
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Toxicology
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The study of poisons, including signs and symptoms of toxicity
7
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Potency vs Efficacy
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Potency refers to the amount of drug necessary to elicit a response. It depends on the affinity of the receptor for the drug and also how efficiently drug-receptor interaction is coupled with response.
Ex. 10 mg of drug A are needed to elicit this level of therapeutic effect, while 5 mg of drug B are needed to elicit this same level of therapeutic affect
- (Textbook): Potency refers to the concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug’s maximal effect. Smaller ED50 means higher potency
Efficacy refers to the ability to produce the maximal desired result (effectiveness)
Ex: Both drugs A and B are effective and have the same efficacy, but drug B is more potent since less is needed to achieve the same effect
8
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Lock and Key hypothesis
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- One of the first accepted hypothesis as to how receptors worked
- Idea was that receptors and ligands had a specific shape, and they fitted together like a lock and key
9
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Induced fit model
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- The second most accepted hypothesis as to how receptors bound to ligands, following the lock and key model
- Idea was that the ligand and receptor didn’t exactly match up in shape, but when the ligand got near the receptor it would cause the receptor to change shape so it could bind
Chem 114A Def:
The enzyme is flexible and can take on a shape that is complementary to the substrate; it does this as the substrate gets closer and interacts with it. Like a hand in a glove model
10
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Conformational Ensembles
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- The most up-to-date theory on how receptors and ligands bind to one another
- Idea is that the receptor exists in the body in different forms; “conformational ensembles.”
- The ligand will bind to the conformation of choice, which will shift the ensemble towards this conformation
11
Q
Decreasing bond strength of different types of bonds that can form between receptor-drug
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Increasing to decreasing strength:
- Covalent
- Ionic
- Hydrogen bonds
- Hydrophobic interactions
- van der Waals forces
12
Q
Generalized Receptors
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-Molecules, such as enzymes and DNA, which are essential to a cell’s normal biological function or replication
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Specialized Receptors
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- Biological molecules that have evolved specifically for intercellular communication
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Agonists
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- Drugs/molecules that bind to a receptor to activate it
- Agonist activation of specialized receptors results in a signal transduction pathway that can be amplified by intracellular mechanisms
15
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Antagonists
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- Drugs/molecules that bind to a receptor but do not activate it
- Compete with agonists to inhibit effect of agonist binding
16
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Allosteric Activator?
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- Binds to a spot other than where the agonist binds that can enhance the action of the agonist
17
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Allosteric Antagonist?
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An antagonist that binds at a spot other than where the agonist binds, preventing a signal from being sent even when an agonist is bound
18
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Features of Receptors
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- There is different tissue distribution of receptors, meaning some tissues have more of a specific receptor than others
- Specificity of binding is not absolute, which can lead to off-target and non-specific effects
- Receptors are saturable b/c there is a limited number
- Agonist activation of specialized receptors results in a signal transduction pathway that can be amplified by intracellular mechanisms
- Drugs can enhance, diminish, or block signal generation or transmission
- Signaling mechanisms of receptors can be unregulated or downregulated, for the most part
19
Q
Specialized Receptor Superfamilies
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- Ion channels
- (Typically) Ligand gated, but can also be voltage gated or second messenger regulated - G-Protein Coupled Receptors
- Receptor tyrosine kinases
- Nuclear Hormone receptors
20
Q
Ligand Gated Ion Channels
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- One of the specialized receptor superfamilies
- Is responsible for fast synaptic transmission
- Found mainly in the brain, peripheral nervous system, heart, and neuromuscular junction
- The receptor itself is an ion channel
- The ligand binds to the receptor which allows it to change its conformation to open up a channel to allow a certain ion to pass through into or out of the cell
- Ex: Nicotinic acetylcholine receptor
- For picture, see lecture 2
21
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GPCR
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G-Protein Coupled Receptors
- One of the specialized receptor superfamilies
- The largest and most important class of receptors in pharmacology
- The actual receptor is a transmembrane receptor that can sense molecules which activates a signal transduction pathway. The signal is sent from the receptor to the g-protein that it is coupled to, which is bound to the inside of the membrane. The signal is replayed/amplified by the g-proteins and they pass the signal onto the effector cyclase, either activating or deactivating it. The effector cyclase can then form a secondary messenger such as cAMP to increase the secondary messenger concentration, which can eventually lead to a cellular response
- Whether we activate or deactivate the effector cyclase depends upon if the receptor interacts with a stimulating or inhibitory agonist, which sends different signals along the cascade
- For picture, see lecture 2
22
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Receptor Tyrosine Kinases
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- One of the specialized receptor superfamilies
-Consist of an extracellular, transmembrane, and intracellular segment - They exist as monomers when not activated and an agonist is not bound, but when the signal molecule binds, this induces dimerization which brings the tyrosine kinases of the two monomers close together so they phosphorylate one another as well as specific proteins, which activates said proteins, promoting a cascade of events leading to a cellular response
- They are able to interact with more than one protein at a time
- These receptors are often targeted by cancer drugs since they play an important role in growth pathways and growth factors
- There are lots of different kinases in the human body that do basically the same thing, just for different proteins and molecules, so it is very difficult to target a specific kinase
Ex: Cytokine receptors - The activated receptor activates proteins that pass into the nucleus to activate transcription of certain genes
- These receptors are used by growth hormones, interferons, and cytokines to regulate nuclear events
- See lecture 2 for a diagram
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Nuclear Hormone Receptors?
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- One of the specialized receptor superfamilies
- Different from the other three superfamilies b/c it exists in the cytosol as opposed to being a transmembrane receptor, meaning its ligand has to get through the membrane via passive diffusion
- Two classes: Intracellular (Class I?) and Nuclear (Class II?)
- All nuclear hormone receptors send a messenger protein to the nucleus to affect transcription
Class I Nuclear Receptor
- Is in the cytoplasm, and typically recognizes hormones
- The ligand enters the cytoplasm and binds to the nuclear receptor (NR) on its ligand binding domain (LBD) to form a complex. This complex then finds another complex and dimerizes. The dimer then enters the nucleus by passing through a nuclear pore. It then typically binds to other molecules like a coactivator or RNA polymerase, and then it binds to the DNA via its DNA binding domains. This activates transcription of the specific gene, and then translation occurs, and the desired protein is made
Class II Nuclear Receptor
- The receptor is already dimerized, inside the nucleus, and bound to the DNA before the hormone comes in
- The hormone binds to the dimerized receptor, knocking off the co-repressor that was bound to the receptor and allowing the receptor to bind to the co-activator and RNA polymerase to transcribe the desired gene
For diagrams see Lecture 2
24
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Intracellular enzymes
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- Enzymes that remain active only within the cell in which it is formed
- This is only one of the many other drug targets aside from the specialized receptors
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cAMP
Cyclic Adenosine Monophosphate
- Is a secondary messenger
- mediates hormonal responses like the mobilization of stored energy, conservation of water by the kidney, Ca2+ homeostasis, and increased rate and contractile
force of heart muscle
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Receptor Desensitization?
- Occurs due to continuous exposure to stimulation by a transmitter or hormone
- Typically occurs mechanistically through phosphorylation of receptors, since phosphorylation is an important regulator of responsiveness
- Primarily occurs with GPCRs
- Two types of desensitization: Homologous and Heterologous
Homologous
- Textbook definition: Homologous desensitization refers to loss of responsiveness exclusively of the receptors that have been exposed to repeated or sustained activation by an agonist
- Dependent upon agonist occupancy of the GPCR
- Agonist-induced phosphorylation of GPCRs is an early event that is important in the process of homologous desensitization
- When the GPCR is phosphorylated it can't interact with its regulatory proteins in the same way and is inhibited from interacting with these proteins and its G-proteins, so it is essentially decoupled from its G-protein
Heterologous
- There appear to be multiple mechanisms of heterologous desensitization
- The GPCRs that undergo this type of desensitization do not need to be bombarded with agonist like with homologous desensitization
- Instead, GPCRs or other receptors nearby to our GPCR of interest become activated by their own ligand and this generates a signal that causes the phosphorylation and thus inhibition of our GPCR of interest
- this is considered "cross-talk"
- Receptor phosphorylation occurs b/c it is a common mechanism of regulating responsiveness
- For diagram see Lecture 2
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Receptor Recycling
- When there is high occupancy of receptors, the cell can internalize the receptors via receptor-mediated endocytosis
- This is one of the ways the body can deal with occupied receptors after being bombarded w/ ligands
- The cell will form vesicles in endocytosis that contain occupied receptors. Two things can then happen. the most common thing to happen is for the receptors and ligand to dissociate via a pH change in the vesicle and then get separated into their own vesicles where the ligands get broken down and the receptor vesicle binds back to the membrane, recycling the receptors. The other, less common thing that can happen is the vesicle with the receptor and ligand still attached can just get recycled back out to the membrane via retro-endocytosis w/out removing the ligand
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Receptor Supersensitivity
- Refers to the phenomenon that occurs when receptors are up-regulated
- I don't think this means the receptor itself becomes more sensitive, just that the cell is more sensitive, which could be due to more receptors being present
- This can be due to
- the exposure of the receptor to an antagonist
- the inhibition of transmitter synthesis or release
- increase in receptor number due to other hormones
- Long term treatment with agonists can lead to a decrease in the number of receptors as the body's way of counteracting. Likewise, the number of receptors can be increased due to long term use of an antagonist
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Selectivity vs Specificity
- No drug is specific, meaning no drug binds to one and only one specific receptor
- Instead, drugs are selective, meaning they are designed to bind more tightly to one or a few specific receptors than to others, meaning they will bind to an elicit a reaction more often in the receptor they are meant to target than to other random receptors, which decreases side effects
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Concentration-response relationship
- The quantification of the amount of drug necessary to produce a given (level of?) response
- The relationship is expressed in two different patterns typically, dependent upon the types/ways of drug response
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Main types of Drug responses
- Graded response and quantal response
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Graded response
- One of the ways the drug can affect the patient
- In this type of response, the affect varies from a minimum to a maximal dependent upon the dose given
- Will see a variable response
- The response is based on drug concentration and receptor occupancy; when concentration of dose is graphed against receptor occupancy (concentration-response curve), the graph takes an hyperbola
- The ED50 of graded response drugs is described as the dose of the drug required to produce 50% of the maximal effect
33
Quantal response
- One of the ways the drug can affect the patient
- Drug affects the patient in an "all or nothing" type way; either if affects them or it doesn't, there isn't really an increase in affect if they are already affected and are given a larger dose
- Ex: sleep drugs that knock you out; either it works or it doesn't
- This response it typically first graphed in a histogram, showing the minimal dose required to elicit a response in each patient. This is carried out by administering the drug to patients in increasing amounts until it has an affect, and then making note of how many people were affected at each dose
- Can also be plotted on a cumulative percentage graph on an arithmetic scale
- The ED50 of a quantal response is described as the dose at which the desired response is elicited in 50% of patients
- The graph shows the dose vs the cumulative number of people who responded at that dose
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ED50
- The dose that elicits an effective response in 50% of people for quantal response
- Also called the median affective dose
- Is defined as for the dose that causes 50% of the maximal effect for drugs with a graded response
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Therapeutic Index
- Relates the dose of the drug required to produce a desired effect to the dose of the drug that produces undesirable effects
- Usually defined as TD50/ED50
- Typically not extremely precise in humans b/c we can't test on humans, but the use of the drug on animals and experience reveals a range of possible toxic doses and effective doses
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TD50
- Called the median toxic dose
| - The dose of a drug that produces a toxic effect in 50% of patients/test subjects
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Types of Agonists
- Full agonists, also what we refer to when we say "agonist": fully activates receptor when bound
- Partial agonist: binds in the same way as a full agonist and with the same pharmacodynamics, but only evokes a partial response
- Partial agonists are said to have a lower intrinsic efficacy. The effect of a partial agonist levels off when all receptors are occupied at a lower response than the maximal response that a full agonist would hit when all receptors are occupied
- Its graph resembles the graph of a full agonist with a noncompetitive antagonist
- Inverse agonist: gives an effect that is opposite of the effects produced by a regular agonist by inverting the response?
- See graph in lecture 3
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Types of Antagonists
- Competitive antagonist: Typically what we think of when we think of antagonists. Competes with the agonist for the same binding site
- Noncompetitive antagonist: These are typically irreversible alkylating agents. They form actual covalent bonds with the receptors and don't dissociate, so those receptors are essentially out of commission, or "dead"
39
Co-dosing with antagonists and agonists
- When agonists and antagonists are present, the law of mass action equation changes a little bit to accommodate the antagonist. In the equation, [D] is the concentration the agonist, Kdis the affinity constant of the agonist, [B] is the concentration of the antagonist, Kb is the affinity constant of the antagonist, [DR] is the concentration of agonist bound to receptor, and [RT] is the receptor concentration.
- Don't need to know the equation, but the presence of the antagonist is taken into account as to how it affect Kd, kind of, and it affects Kd by making the apparent Kd appear larger, meaning more agonist is needed to produce a given response than had the antagonist not been present.
- When looking at the concentration-response curve, the presence of an antagonist shifts the curve to the right (parallel rightward shift) for the same reasons as described above
- The magnitude of rightward shift is dependent on the concentration of antagonist, which is variable, divided by its affinity constant, which is fixed.
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Law of mass action
- Describes the relationship between proportion/extent of receptor occupancy to concentrations of receptors and drug
[DR]/[RT]= [D]/([D] + Kb) where [D] is the concentration of drug or agonist, Rt is the total number of receptors, Kb is the equilibrium dissociation constant, and [DR] is the concentration of receptors bound to drugs.
[DR]/[RT] is the proportion of receptors bound, also called the fractional occupancy
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Kd
- The equilibrium dissociation constant, also called the affinity constant.
- It is defined by the concentration of a drug at which half of the receptors are occupied
- Is a reflection of structural affinity of the drug and its receptors
- A high Kd means a lower affinity, and a low Kd means a higher affinity
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How to tell the difference between a partial agonist and an antagonist?
- A partial agonist still shows activity, just less than a typical agonist. An antagonist will show no activity.
- Drugs with full efficacy are agonists
- Drugs with partial efficacy are partial agonists
- Drugs with zero efficacy are antagonists
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Co-dosing with both partial agonists and agonists
- Treating with both, with both affecting the same receptor, can allow you to decrease the maximal response of the agonist, b/c it will be competing with the partial agonist and the partial agonist won't elicit as much as a response as the agonist when it binds
- The more partial agonist you use, the lower the maximal response b/c the competition has increased
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How can we achieve a maximal response when only a small fraction of receptors are occupied by an agonist?
- By spare receptors
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Spare receptors
- Lead to signal amplification and can allow us to achieve maximal response without full receptor occupancy
- Spare receptors make a tissue more sensitive to an agonist without changing its affinity for the receptor
- Receptors are said to be “spare” for a given pharmacologic response if it is possible to elicit a maximal biologic response at a concentration of agonist that does not result in occupancy of the full complement of available receptors.
- This phenomena may occur b/c the receptors are spare in number relative to the total number of downstream signaling mediators present in the cell, so even though the receptors may not be at full occupancy, all downstream mediators are being used.
- With spare receptors, ED50 < Kd b/c we achieve over half the maximum effect without having bound half of the receptors since there are more receptors present than downstream mediators
- There can be different levels of spare receptors in different parts of the body. In this way, spare receptors are also responsible for tissue specific actions of agonists
- The presence of spare receptors shifts the concentration-response graph to the left
- The more receptors there are in a tissue, the more potency the drug has in that tissue, and the further the curve is shifted to the left
- Makes it difficult to distinguish between full agonists and partial agonists sometimes, b/c a drug may appear to be a partial agonist in one tissue but then appear to be a full agonist in another b/c it has spare receptors (see page 13 in Brody's)
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Coupling
- The overall transduction process that links drug occupancy of receptors to pharmacological response
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Intrinsic Activity
- Used to describe the ability of a tissue to respond to agonist stimulation. Intrinsic activity is highly context dependent; different tissues can have different proportions fo spare receptors AND different downstream amplification methods
- A drug can be a partial agonist in efficacy, but a full agonist in intrinsic activity when spare receptors are present
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What tissue sensitivity depends on
- The sensitivity of a tissue or cell at a given concentration agonist depends not only on the affinity of the receptors for the drug, but also on the degree of spareness, or how many spare receptors there are
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Therapeutic window
The range between the minimum toxic dose and the minimum therapeutic dose
