DSA 1 Flashcards
What is pharmacodynamics?
How the drug affects the body MOA, type of receptor it binds to, and dose-response curves
What is pharmacokinetics
How the body affects the drug; ADME (absorption, distribution, metabolism and elimination)
Receptor + drug => activates receptor => initiates biochemical effects => cause drug effects Receptors have a _______ role.
regulatory
Inert binding site is?
where a drug binds, however it does not change fx.
Ligand is a?
hormone or a drug that binds to a receptor.
If a drug-receptor bind covalently, the interaction is ______.
Irreversible
If a drug-receptor binds non-covalently, the interaction is ________.
Reversible
If a drug-receptor bind covalently, removal of the drug or re-activation of the receptor requires what?
REmake a receptor or remove the drug using an enzyme
Most drugs bind to receptors ______
NON-covalently
List non-covalent interactions from strongest => weakest.
- Ionic: [position ion] + [negative ion] - Hydrogen bonds: - Hydrophobic interactions: hydrophobic regions of drug + receptor interact.
What 3 factors describe how well a drug and receptor interact?
- Affinity 2. Selectivity 3. Intrinsic activity
What is affinity?
how well a drug binds to a receptor
High affinity: _____ interaction and ____ drug is needed to create a response.
good LESS
Low affinity: ____ interaction and ___ drug is needed to make a response.
BAD MORE
What is KD?
KD (Equilibrium dissociation constant) is the concentration of the drug where 50% of the receptors are occupied.
What is the relationship between affinity and KD?
High affinity = lower KD Lower affinity= higher KD because we need more the drug to occupy 50% of the receptors
Selectivity of a drug is? What determines a drugs selectivity
Selectivity is the degree to which a drug acts on a given site relative to other site (within a range) It is determined by the drugs affinity at different binding sites.
What is a intrinsic activity?
The ability for the drug to produce a physiological response when it binds to a receptor
Which have intrinsic activity; agonist or ANT?
Agonists: not ANT
What happens when a AGO binds to receptor
=> stabilizes it in active confirmation => cause a physiological response
ANT do not have physiological response. What do they do then?
They do not change the function but they bind => if ago is present, prevent the activation.
what do ANT do when an AGO is NOT present?
no effect
Full AGO: _____ activate receptors, produce a ______ effect when bound to all receptors and have _____ intrinsic activity.
Fully; max; max
Partial AGO ______ activate receptors, produce a ______ effect when bound to all receptors and intrinsic efficacy _________.
partially sub-max IA will depend on the drug but it is always sub-max
A partial AGO will have _____ affinity for both Ri and Ra forms
intermediate
What do inverse AGO do?
Has the opposite effect of a full/partial AGO; decrease receptor signaling, decrease response, its IA will inhibit the function of the receptor
ANT has _____ affinity for both Ri (inactive receptor that produces no effect) and Ra (active receptor that can activate downstream mechanisms that produces a small observable effect, even in the absence of ligands) and have ____ level of constitutive activity.
equal; same
___________ is have action at the same reeptor as endogenous ligands or AGO drugs ______ occurs when a chemical ANT prevents drug from binding
Pharmacologic ANT Chemical ANT
Inverse AGO have a higher affinity for the ____ form
Ri
What are the types of pharmacologic ANT?
- Competitive ANT 2. Non-competitive ANT; includes both irreversible ANT and allosteric ANT.
_________ irreversibly (covalently) and block where AGO bind.
Irreversible ANT
________ bind to ANOTHER site than the AGO site to prevent or reduce the AGO from binding or activation of the receptor.
Allosteric ANT
Competitive ANT: higher concentrations of the AGO are required to displace the ANT and cause an effect (shifts to the ____)
right
EC50 is what?
concentration of a drug that gives HALF of the max response.
What is Vmax
max rate of reaction when all receptors are bound
Competitive ANT: EC50 ____; Vmax ____
EC50 increases Vmax: does not change
Noncompetitive ANT: EC50 _____; Vmax ____
EC50 does not change Vmax: decreases
The dose-response curve makes a _______ when plotted arithmetically.
hyperbolic curve
- The dose-response curve makes a ________ curve when it is plotted using a logarithm: most common!!!!
Sigmoidal
- Describe the dose-response curve parameters, such as ED50 and Emax.
Emax: max effect that a drug can make
ED50 (effective dose): dose of the drug that makes 50% of the max effect
Distinguish between quantal and graded responses and recognize when a response is graded vs. quantal.
- Graded response (how much) of a drug will produce a certain response; it is usually a mean in a population and the magnitude will vary.
- Quantal response (all or none/binary) asks if a response will occur and requires a pre-defined response and is used to describ e a frequency of a response in a large population
A ____ response is seen an a individual/mean value in a population and increases with dose.
Graded response
_______ response is seen in a population and is either [present/absent] in a single person.
Quantal response
What 2 questions do quantal responses answer?
- 1. In how many (in how many people will death occur)
- 2. Does the response occur or not (yes or no)
What questions do graded responses answer?
How much
Usually a mean value in a population or a single person
Non-cumulative quantal dose-response curve: shows us what?
the # of ppl that response AT a dose and ONLY at that dose
- 20% of people in the population who take 10 mg of a drug will die
Cumulative quantal dose-response curve shows us what?
of people that response at a dose and at ALL doses lower than those dose.
- 20% of people in population who take up 10 mg of a drug will die.
Median effective dose (ED50) is?
the dose where 50% of the population react to the drug
TD50
median toxic dose
LD50
median lethal dose
TI
Therapetuic index (TI) calculates the safety of a drug
Higher TI=safer
TI= TD50/ED50
therapeutic window
Range of doses of a drug or its concentration in the body that are safe and effective
Potency
the dose of drug needed to create a specific pharmacological effect
More potent drugs have _____ ED50
lower
More potent drugs will have a _____ affinity and a _____ KD
higher
lower
On a sigmoidal DR curve, potency increases as EC50 ____
Potency increases going from _____
decreases
R => L
Efficacy is?
can be measured by Emax;
it is the max effect a drug can produce.
Efficacy is related to?
What is it used to determine?
Total number of receptors that are available for drug to bind to.
Determine the magnitude of clinical effect
High ____ => more effective
High Emax
On a DR, efficacy increases as a curve _____
goes up
What do drugs target? (6)
1. Membrane receptors
2. Cytoplasmic receptors
3. Nuclear receptors
4. Ion channels,
5. Transport proteins
6. enzymes
Kinases do what?
covalently phosphorylate a protein using a phosphate lost from ATP => ADP
Transcription factors (TFs) bind to DNA using its _________ (defining feature) at the ______________, located near coding sequence of gene, and control transcription from DNA => RNA
- DNA-binding domain
- Response element (enhancer or promotor region)
TF MOA?
Promote the recruiment of RNA polymerase to genes via activators
Inhibit the recruitment of RNA polyermase to genes via inhibitors
1/3 of drugs act on GCPR, which are heterotrimeric (alpha, beta and y subunits)
What is the G-protein cycle?
- AGO binds and activates the GCPR
- Promotes release of GDP from alpha protein
- GTP then binds to nucleotide binding site
- Alpha-protein + GTP => causes G-protein to bind to the effector enzyme or ion channel.
- Hydrolysis of GTP -> GDP => signal terminated.
which G-protein:
+ AC and Src tyrosine kinases
Gs
What does Gi Gprotein do?
- Inhibit AC 13, 5 and 6
- Activate tyrosine kinase Src
What does Gq do?
+ PLC CB
G 12/13 does what?
+ Rho GTPases => Cytoskeletal rearrangements
Describe the process of densitization.
- AGO binds to cell => cAMP
- Continued prescence will reduce cAMP ersponse after a few minutes.
- If AGO is removed after a short time, cells revoer FULL responsiveness to an additional AGO “resensitization”.
- Resensization does NOT occur if the cells are exposed to AGO repeatedly or for a long time
What is the process of resensitization?
- AGO binds to a receptor => initiates signaling by promoting the receptor interaction with G protein
- GRK (G-protein-coupled receptor kinase) phosphorylates [AGO + receptor], preventing the Gs protein from binding to the receptor and promoting B-arrestin to bind.
- Receptor-arrestin complex bind to coated pits, which internalizes the receptor.
- AGO dissociated from internalized receptor => reduces B-Arr binding affinity, allowing phosphotase to dephosphorylate the receptor
- Receptor returns to plasma membrane
What promotes the DOWN-regulation of a receptor, instead of densitization?
Following the processes that occured before, if the AGO does not dissociate from the internalized receptor => B-arrestin will stay bound => receptor is broken down by lysosomes.
27. Describe signaling involving cyclic AMP system and the role phosphodiesterase in regulating the intracellular concentration of this signaling intermediate.
- AGO binds to GCPR
- +Gs
- +AC (converts ATP => cAMP
- cAMP activates PKA
PDE hydrolyzes cAMP to 5’AMP
Gq: Gq => PLC => PIP2 will split into IP3 and DAG
IP3 causes Ca2+ to be released from ____
What does DAG do?
SR
+ PKC
What receptors trasmit the action of growth factors?
RTKs (receptor tyrosine kinases)
Describe receptor tyrosine kinase signaling,
- RTK is a transmembrane receptor: GFs bind (IGF, insulin, VEGF, EFG, NGF and PDGF),
- Receptor converts from inactive monomeric state => active dimeric state, where 2 receptor polypeptides bind non-covalently.
3. Cytoplasmic domain is phosphorylated on tyrosine resides
4. Activate and phosphorylates substrates (ATP-ADP)
Receptors coupled to JAK kinases are coupled to JAKs, ______ tyrosine kinases.
cytosolic tryrosine kinases
receptors coupled to JAKs trasmit the effects of what?
1. Growth hormones (somatotropin)
2. Erythropoeitin
3. Leptin
4. Interferons
5. IL 2-10 and 15
ONce JAK kinases are activated, what do they do?
- Phosphorylate signal transducers and activate transcription (STAT) molecules
- STAT dimers => go to nucleus => regulate transcription
Nuclear receptors are ______ TF that do what?
What binds to them?
Ligand-activated
modulate gene expression
-lipophillic molecules (steroids, thyroid, vitD/A, lipid mediateors)
Name nuclear receptors
1. androgen receptor
2. estrogen receptor
3. progesterone receptor
4. Glucocorticoid receptors
5. Mineralcorticoid receptors
When do hormones that bind to nuclear receptors cause effects?
How long do they last?
Produce effects after a LAG period of several hours or days
Effects can persist even afer concentration of AGO is 0
Drug A is a partial AGO. Drug B is a full AGO. Thus, drug A has a _____ Emax than drug B.
lower
In the absence of other drugs, pindolol causes increase in HR by activating B-AR. When highly effective B-AR stimulants are present, pindolol causes a decrease in HR. Thus, it should be classified as a _______
Partial AGO
Competitive ANT: Agonist EC50 ____; Emax _____
Noncompetitive ANT: EC50 ______ but AGO Emax ______.
Competitive ANT: Agonist EC50 increases; Emax does not change
Noncompetitive ANT: EC50 does not change but AGO Emax decreases.
