Intro to Pharmacodynamics Flashcards
What is pharmacokinetics?
Effects of the body on drugs: absorption, distribution, metabolism, elimination.
What is pharmacodynamics?
Effects of drugs on body: drug receptors, dose response curves, mechanisms of drug actions.
Inert binding site
A component of the system that a drug binds and does not change the function.
Covalent bonds in drug interactions are:
They are irreversible.
Drug removal/receptor re-activation requires re-synthesis of the receptor or enzymatic removal of the drug.
Non-covalent bons in drug interactions are:
Reversible.
Most drugs bind to receptors this way.
Strongest to weakest non-covalent bonds (3)
Ionic bond > hydrogen bond > hydrophobic interactions
3 parameters describing the interaction of a drug w/ a receptor
Affinity
Selectivity
Intrinsic activity
Affinity
How readily and tightly the drug binds to its receptor.
What is Kd?
What is the unit for Kd?
What does a low/high Kd mean?
Equilibrium dissociation constant (describes affinity).
Drug conc. at which 50% of drug receptor binding sites are occupied w/ the drug.
Kd is expressed in molar conc. (micromoles, nanomoles, etc.).
Low -> higher affinity
High -> low affinity
How do you find Kd mathematically?
L + R -> LR
Kd = ([L][R])/[LR]
Reactants over products
How is selectivity measured?
By comparing affinities of a drug to different receptors.
What is a drug’s intrinsic activity?
The ability of a drug to change a receptor function and produce a physiological response upon binding to a receptor.
Do agonists have intrinsic activity?
Yes.
They bind to a receptor and stabilize it in a particular conformation and produce a response.
Do antagonists have intrinsic activity?
No.
They bind to the receptor but do NOT change its function. They prevent activation of the receptor in the presence of an agonist. There is no pharmacological effect in the absence of an agonist.
What are inverse agonists?
They produce an effect opposite to a full or partial agonist.
- decrease receptor signaling
- decrease response at receptors
- intrinsic activity is present and related to the inhibition of receptor function
Competitive antagonists
Compete w/ endogenous chemicals or agonist drugs for binding the receptor.
Can be outcompeted.
Irreversible antagonists
Irreversibly bind to and occlude the agonist site by forming covalent bonds.
Allosteric antagonists
Bind to a site other than the agonist site to prevent or reduce agonist binding.
What happens to EC50 and Emax in competitive antagonism?
EC50 increases
Emax does not change
What happens to EC50 and Emax in noncompetitive antagonism?
EC50 does not change
Emax decreases
Nonreceptor antagonists include:
Chemical and physiologic antagonists
Arithmetically, the dose-response curve is:
More commonly, the dose response curve is:
Hyperbolic curve
Sigmoidal curve (take the log)
What is a graded response?
Answers “how much?”
Magnitude of a response varies continuously.
Usually represents the mean value within a pop. or a single subject.
What is a quantal response?
All or none, yes or no, etc. Answers “does the response occur at all?”
Requires a pre-defined response (death, falling asleep, etc.)
Used to examine the freq. of a response within a large group.
Quantal dose-response curve
Relates dose of a drug to the freq. of a response.
Bell-curve looking.
Non-cumulative quantal dose response curve
Number or percent of individuals responding at a dose of a drug and only at that dose.
Cumulative quantal dose response curve
Numer or percent of individuals responding at a dose of a drug and at all doses lower than that dose.
ED50
TD50
LD50
Median effective dose
Median toxic dose
Median lethal dose
Therapeautic index =
TD50/ED50
The higher the TI the safer the drug
Drugs with what kind of affinity tend to be more potent?
What is it represented by?
What does a low ED50 mean?
What does it determine?
High affinity (low Kd)
ED50
The more potent the drug
Determines the drug dose that will be used clinically
What is potency?
The amt. of a drug required to produce a specific pharmacological effect.
What is efficacy?
The maximal pharmacological effect that a drug can produce.
What represents efficacy?
What is efficacy related to?
What does it determine?
Emax (the greater the Emax, the more efficacious the drug.
Related to the amt. of receptors available.
Determines the magnitude of clinical effect.
5 major classes of drug targets
Membrane receptors Nuclear receptors Ion channels Transport proteins Enzymes
How do protein kinases work?
Examples (2)
Modify protein by covalently attaching PO4- to an AA residue.
Ser-Thr kinases, Tyr kinases
Gs second messenger and effect
Adenylyl cyclases -> AC activation
Gi second messenger and effect
Adenylyl cyclases -> AC inhibition
Gq second messenger and effect
Phospholipase C -> PLC activation
G12/13 second messenger and effect
Rho GTPases -> cytoskeletal rearrangements
Gs effects:
Activates all isoforms of AC and Src try kinase
Gi effects:
Inhibits AC 13, 5, 6.
Activates Src tyr kinase.
Gq effects:
Activates phospholipase C-beta
G12/13 effects:
Rho GTPases
GRK and beta-arr
GRK improves beta-arr binding and stops the signaling cascade
Receptors w/ intrinsic tyrosine kinase activity (RTKs) (6)
IGF-1 Insulin VEGF - vascular endothelial EGF - epidermal NGF - nerve PDGF - platelet-derived
What are JAKs?
What are 5 examples of hormones/cytokines that effect it?
A family of cytosolic tyr kinases.
GH (somatotropin) Erythropoietin Leptin Interferons ILs 2-10, 15
When do nuclear receptors produce their effects?
What is unique about them?
After a lag period.
The effects can persist after the agonist conc. has been reduced to 0.
What is the MOA of a glucocorticoid?
Hsp 90 binds the 3 domained receptor in the absence of the hormone and blocks folding into active conformation. When the hormone binds, hsp90 dissociates and permits conversion to the active configuration.
Full agonists (3)
Fully activate R
Produce max. effect when all Rs occupied
Max. intrinsic activity
Partial agonists (3)
Partially activate the R upon binding
Produce sub-max effect when all Rs are occupied
Intrinsic activity varies depending on drug, but always sub-max.
