1: Pharmacodynamics 1 Flashcards
pharmacodynamics vs. pharmacokinetics
dynamics: drug effects on the body - dose-response relationships and drug-receptor interactions
kinetics: the body’s effects on the drug - ADME (absorption, distribution, metabolism, elimination) - [plasma] over time
what is biopharmaceutics?
science of how you package a drug to get it where it needs to go (we won’t talk about this much)
what is the cornerstone of pharmacology?
the receptor = drug target
definition of drug side effect
an unwanted or bothersome effect of a drug usually related to the main effect
definition of drug toxic effect
a harmful or adverse effect of a drug
- generally not related to the main effect
- often related to excessively high drug concentration
factors that affect the magnitude of response to drug therapy
- dose administered
- concentration at site of action
- duration in which the drug remains at the site of action
time-action curve: two important questions for every drug
- How quickly will the drug act?
- How long will the drug effect last?
- time to onset of therapeutic effect
- minimum effective concentration
- peak concentration
- duration of action
- residual effect
what type of function do drugs modify?
cellular function only
3 potential types of sites of drug action
- extracellular
- intracellular
- on the cell surface
examples of extracellular sites
- neutralization of excessive gastric acid by antacids
- heparin in preventing blood coagulation
examples of intracellular sites
- drugs used to treat infections
- drugs used for cancer chemotherapy
- hormones such as estrogen
examples of cell surface sites
many drugs act by combining with receptors on the cell surface
- ACh and muscarinic receptors
- catecholamines and alpha- and beta-receptors
- histamine and H2 receptors
what determines the quantitative relationship b/w dose/concentration of drug and pharmacologic effects?
receptors
what determines the selectivity of drug action?
receptors - size, shape, and electrical charge of a drug molecule + changes in the chemical structure of a drug
definition of agonists
drugs that bind to a receptor and stimulate a biological response
definition of antagonists
drugs that bind to a receptor without altering receptor function, but prevent other drugs/substances from binding (such as agonists)
definition of inverse agonists
- look like antagonist, but changes receptor to inhibit basal activity of that receptor
- not many drugs use this action
macromolecular nature of most drug receptors
proteins
- regulatory proteins (GPCRs, ion channels, transporters)
- enzymes
- transport proteins
- structural proteins
concentration-effect curves of agonists
- responses to [low] increase proportionally (graded response - but there are some exceptions (bimodals))
- as doses increase, the incremental response decreases
- may become saturated = hallmark of a receptor-mediated response
definition of effective concentration
EC50
-concentration at which you get 50% of the maximal response
law of mass action for drugs
[D] + [R] [DR] –> effect
k1 = association rate constant
k-1 = dissociation rate constant
the effect of a drug is directly proportional to the amount of drug-receptor complex formed
rate of association? rate of dissociation?
association: k1 [D][R]
dissociation: k-1 [DR]
definition of dissociation constant
KD
-measure of how tightly the drug binds to the receptor
= [D][R]/[DR] = k-1/k1 (in moles)
-at KD, half the receptors are bound by drug
-allows you to compare affinities of different drugs
the lower the KD, the ______ the affinity
higher
relationship between occupied receptor B and drug concentration C
occupied receptor B = (C x Bmax)/(C + KD)
law of mass action: assumptions (3)
- the binding is totally reversible
- D and R only exist as free and bound
- all receptor sites are considered to have equivalent affinity for D and to be independent
definition of potency
- the dose of a drug required to produce a particular effect of given intensity
- comparison based on doses that produce the SAME effect (usually ED50)
definition of affinity
- the ability of the drug to interact with the receptor
- measured by KD
- one of the determinants of potency
definition of efficacy
- the biological response resulting from the drug-receptor interaction/ magnitude of response from drug-receptor interaction
- maximal efficacy is often limited by toxicity
- includes how well the enzyme can convert the DR combo into the final product
which is more important as a drug property: potency or efficacy?
efficacy
however, you also hope for good efficacy b/c less chance for adverse effects
[D] + [R] [DR] —————> effect
(potency) (efficacy)
definition of a partial agonist
- elicits a biological response, but it is not a full response, even at full receptor occupancy
- cannot produce same maximal effect as a full agonist, regardless of concentration used
- may competitively inhibit the response of a full agonist
- mechanisms complex, but probably related to drug binding in inactive form of receptor
definition of receptor antagonism and three types
a drug-receptor interaction that interferes with or prevents the development of a drug response by an agonist
- competitive
- mixed
- irreversible
definition of competitive antagonism
- antagonist combines with the same site on the receptor as the agonist
- antagonism can be reversed by increasing dose of the agonist (outcompetes the antagonist)
- has affinity but lacks significant intrinsic activity (efficacy)
how does a competitive antagonist shift the dose-response curve?
shifts the curve to the right in a parallel fashion (shape does not change) - indicates a reduction in the effective potency of the agonist
magnitude of shift to the right is proportional to the [antagonist]
concept of spare receptors
- when the maximal response can be elicited by an agonist at a concentration that does not result in 100% occupancy of available receptors
- important in the action of irreversible antagonists
how does an irreversible antagonist shift the dose-response curve in the presence of spare receptors?
- at lower [antagonist], you get a parallel, right shift and still get maximal response b/c there are more receptors present than are needed for full response
- but reach a critical level of receptors required for maximal response: then as [antagonist] increases, the slope of the line decreases and you get a down shift (in a sense) of the line - with lessened maximal effect
definition of noncompetitive antagonists
- antagonist produces its effect at a site of the receptor other than the site used by the agonist
- agonist and noncompetitive antagonist do NOT compete with one another for a single binding site
- antagonism cannot be completely reversed by increasing the [agonist]
- increasing [antagonist] increases KD and decreases Emax of the agonist
- reduces both the efficacy and the affinity (increased KD) - right shift of the EC50
describe the log dose-response curve in the presence of a noncompetitive antagonist
- shifted to the right
- as the dose of noncompetitive antagonist increases, the slope of the agonist curve and maximal response obtained are progressively decreased
- at very high [antagonist], no amount of agonist can produce a response
comparison of reversible vs. irreversible antagonists
- an irreversible antagonist will usually bind to the same site as the agonist, but will not be readily displaced
- irreversible inhibition is generally caused by covalent reaction b/w antagonist and receptor
- inhibition persists even after an irreversible antagonist is removed
definition of positive allosteric activators
=positive allosteric modulator (PAM)
- can increase potency and/or efficacy
- synergistic with agonists
definition of negative allosteric activators
= negative allosteric activator/modulator
- can decrease potency and/or efficacy
- ex: noncompetitive antagonists
definition of functional/physiological antagonism + example
- two drugs influence a physiological system but in opposite directions
- each drug is unhindered in the ability to elicit its own characteristic response
ex: ACh on BP (lowers it) vs. epinephrine on BP (raises it)
definition of chemical antagonism
- a chemical reaction occurs b/w 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
ex: Ca-antacids chelate tetracycline antibiotics; sodium nitrite inactivates cyanide
