exam 2 lecture objectives Flashcards
(36 cards)
the study of the biochemical and physiological effects of drugs and the mechanisms of their actions, including the correlation of their actions and effects with their chemical structure; what the drug does to the body
pharmacodynamics
science of interactions of chemical compounds with biological systems; how drugs act, where they act, etc
pharmacology
the study of the absorption, distribution, biotransformation, and elimination of xenobiotics; what the body does to the drug
pharmacokinetics
describe the characteristics of drugs
defined by their actions
most act on receptors (exceptions are chemical antagonists or osmotic agents)
endogenous drugs (hormones or neurotransmitters) or xenobiotics
includes poisons/toxins (“the dose makes the poison”)
solids, liquids, gases
ions to larger proteins/antibodies/vaccines
covalent, electrostatic, hydrophobic interactions
drug shape and rational drug design for receptor specificity (enantiomers and structural studies)
identify the sites of drug action, including receptors
the drug receptor (active site) is the cornerstone of pharmacology, explains how the organism interacts with a drug and initiates chain of biochemical events
orthosteric site is where the drug binds, also the receptor (agonist (partial and inverse), competitive inhibitor, antagonist)
allosteric site is a site other than the active site that the drug may bind to (PAM or NAM)
relate affinity to the law of mass action and receptor occupancy
the effect of a drug is directly proportional to the amount of drug-receptor complex formed
KD= [D][R]/[DR] (Koff/Kon)
the lower the KD the higher the affinity
when D occupies half of the receptors, the concentration of unoccupied receptors equals the concentration of occupied receptors, [R]=[DR], so KD=[D]
KD is the concentration of ligand that will bind half the receptors at steady state
outline components in a receptor binding assay
Bmax: total number of receptors on given cell or tissue (may be changed by drug or pathology)
KD: affinity of ligand for receptor, identified at 1/2 Bmax
IC50: concentration of drug required to occupy 50% of receptors (smaller IC50= higher affinity)
use the principles of receptor binding to measure affinity
affinity is the ability of the drug to interact with the receptor
a single drug may have different affinities for different receptors
KD= affinity of receptor
smaller KD= higher affinity= more likely to bind to receptor
use graphical data for pharmacological profiling
the IC50 value is determined from experimental data
Ki is calculated using Cheng-Prusoff equation
relative affinity is relative to the compound of interest
apply receptor affinity to receptor selectivity
higher affinity= higher selectivity
describe the relevance of Bmax to drug action
estimated number of receptors in a given tissue
determines through saturation binding studies
independent of the ligand
can influence downstream signaling events
describe the difference between agonist and antagonist binding
binding of an agonist results in an induced fit that activates the receptor
binding of an antagonist results in a different induced fit that does not activate the receptor
identify and compare dose response curves for each type of ligand in the ligand spectrum
efficacy from -100% to 100%:
full inverse agonist (-100%)
partial inverse agonist
silent antagonist (no response)
partial agonist
full agonist (100%)
super agonist
use graphical data to compare potency and efficacy
potency is the dose of a drug required to produce a particular effect of given intensity
increasing potency: sigmoidal curve shifts to the left, decreasing ED50
efficacy is the biological response resulting from the drug-receptor interaction
increasing efficacy: curve shifts up, maximal effect increases
describe the concept of a partial agonist and apply to drug action
partial agonists produce a reduced response even at full receptor occupancy
cannot produce the same maximal effect as a full agonist regardless of concentration
may inhibit competitively the response to a full agonist
inert receptor-agonist complex forms, enters flip state before opening, and channel opens
partial agonists are less effective at inducing the flip state but open the channel just as quickly, decreasing drug action
describe the actions of inverse agonist
produces the opposite response of an agonist, causing decrease in response
may block the active site and cause G protein to release from the receptor
compare reversible competitive and irreversible, non-competitive inhibition
competitive: binds to the same active site as the agonist, can be reversed by increasing the dose of the agonist, log-dose response causes curve to shift right (reduced potency but no change in efficacy)
non-competitive: binds to a site other than the active site where agonist binds (do not compete), cannot be completely reversed, increases KD and decreases Emax, log-dose curve shifted right and max decreased, at very high concentrations, no amount of agonist can produce a response
irreversible: will usually bind to the same site as the agonist but will not be readily displaced, generally caused by covalent reaction between antagonist and receptor, inhibition persists even after removal, duration of action dependent on receptor turnover
use the concept of spare receptor to explain drug responses
when maximal response can be elicited by an agonist at a concentration that does not result in 100% occupancy of available receptors
increase in potency but not efficacy
system/tissue dependent
describe chemical and functional antagonism
functional: two drugs influence a physiological system but in opposite directions, each drug is unhindered in the ability to elicit its own response
chemical: a chemical reaction occurs between an agonist and an antagonist to form an inactive product, agonist is inactivated in direct proportion to the extent of the chemical reaction with the antagonist
describe the mechanisms of allosteric modulators and their potential benefit in drug therapy
bind at sites other than the active site
positive allosteric modulators increase signaling
negative allosteric modulators decrease signaling
identify and differentiate between the five classes of receptors
- intracellular receptors- lipid soluble ligand crosses the cell membrane and acts on an intracellular receptor; stimulate the transcription of genes by binding to specific DNA sequences near the gene whose expression is to be regulated (ex: steroids, vitamin D, thyroid hormone)
- cytokine receptors- activation leads to activation associated tyrosine kinase molecules (JAK); phosphorylation of signal transducers and activators of transcription (STAT); STAT dimers travel to the nucleus to regulate transcription
- protein tyrosine kinases- usually act as dimers; receptor consists of an extracellular hormone-binding domain and a cytoplasmic enzyme domain with protein tyrosine kinase activity; spans the lipid bilayer one time; binding induces a conformational change; tyrosine phosphorylation allows receptors to recruit proteins and signal for the effects of ligands
- ion channels- voltage-gated regulate the flow of ions through plasma membrane channels (Na+, Ca2+, K+) regulated by phosphorylation and G proteins; many of the most useful drugs act by mimicking or blocking the actions of endogenous ligands that regulate the flow of ions through plasma membrane channels (acetylcholine); cellular response is rapid in milliseconds
- G protein-couples receptors- ligands act by modulating effectors and/or intracellular concentrations of second messengers; R-G-E; extracellular ligand detected by cell surface receptor (R); receptor activates G protein (G) on cytoplasmic face; activated G protein changes the activity of an effector (E) element (enzyme of ion channel); response amplified
describe the effects of allosteric modulators on ion channels and GPCRs
ion channels- an allosteric modulator may cause a conformational change and hold the channel open of closed; may mimics or block the actions of endogenous ligands
GPCRs-
describe the features for G protein activation
extracellular ligand is detected by the cell surface receptor
the receptor triggers the activation of a G protein on the cytoplasmic face of the plasma membrane
the activated Ga or Gby protein then changes the activity of the effector element
the effector often changes the concentration of the intracellular second messenger which produces the effect
results in a greatly amplified response
Ga-GDP is inactive -> Ga-GTP or Gby can activate the enzyme or channel-> enzyme or channel results in release of second messengers
know the effectors of subtypes of G proteins
Gas: stimulates adenylyl cyclase
Gai: inhibits adenylyl cyclase
Gaq: stimulates phospholipase C
Ga12/13: rho guanine exchange recruitment
Gby: inhibits or stimulates adenylyl cyclase, GRK recruit, stimulates PLC, PI3K, stimulates ion channels
