Chap 2 Pharmacodynamics Flashcards
Receptor
A molecule to which a drug binds to bring about a change in function of the biologic system
Inert binding molecule or site
A molecule to which a drug may bind without changing any function
Receptor site
Specific region of the receptor molecule to which the drug binds
Spare receptor
Receptor that does not bind drug when the drug concentration is sufficient to produce maximal effect; present when Kd > EC50
Effector
Component of a system that accomplishes the biologic effect after the receptor is activated by an agonist; often a channel, transporter, or enzyme molecule, may be part of the receptor molecule
Agonist
A drug that activates its receptor upon binding
Pharmacologic antagonist
A drug that binds without activating its receptor and thereby prevents activation by an agonist
Competitive antagonist
A pharmacologic antagonist that can be overcome by increasing the concentration of agonist
Irreversible antagonist
A pharmacologic antagonist that cannot be overcome by increasing agonist concentration
Physiologic antagonist
A drug that counters the effects of another by binding to a different receptor and causing opposing effects
Chemical antagonist
A drug that counters the effects of another by binding the agonist drug (not the receptor)
Allosteric agonist, antagonist
A drug that binds to a receptor molecule without interfering with normal agonist binding but alters the response to the normal agonist
Partial agonist
A drug that binds to its receptor but produces a smaller effect (Emax) at full dosage than a full agonist
Constitutive activity
Activity of a receptor-effector system in the absence of an agonist ligand
Inverse agonist
A drug that binds to the non-active state of receptor molecules and decreases constitutive activ- ity (see text)
Graded dose-response curve
A graph of the increasing response to increasing drug concentration or dose
Quantal dose-response curve
A graph of the increasing fraction of a population that shows a specified response at progres- sively increasing doses
EC50, ED50, TD50, etc
In graded dose-response curves, the concentration or dose that causes 50% of the maximal effect or toxicity. In quantal dose-response curves, the concentration or dose that causes a speci- fied response in 50% of the population under study
Kd
The concentration of drug that binds 50% of the receptors in the system
Efficacy, maximal efficacy
The largest effect that can be achieved with a particular drug, regardless of dose, Emax
Potency
The amount or concentration of drug required to produce a specified effect, usually EC50 or ED50
Graded dose-response and dose-binding graphs
FIGURE 2–1 Graded dose-response and dose-binding graphs. (In isolated tissue preparations, concentration is usually used as the measure of dose.) A. Relation between drug dose or concentration (abscissa) and drug effect (ordinate). When the dose axis is linear, a hyperbolic curve is commonly obtained. B. Same data, logarithmic dose axis. The dose or concentration at which effect is half-maximal is denoted EC50, whereas the maximal effect is Emax. C. If the percentage of receptors that bind drug is plotted against drug concentration, a similar curve is obtained, and the concentration at which 50% of the receptors are bound is denoted Kd, and the maximal number of receptors bound is termed Bmax.
graded dose-response curve
A graph of increasing response to increasing drug concentration or dose
What parameters are created from the graded dose-response curve
The efficacy (Emax) and potency (EC50 or ED50) parameters are derived from these data.
The smaller the EC50 (or ED50), the greater the potency of the drug.
(ED50)
median effective dose (ED50)
(TD50)
median toxic dose (TD50)
(LD50)
median lethal dose (LD50)
maximal efficacy is measured with ?
- greatest effect (Emax) an agonist can produce if the dose is taken to the highest tolerated level
- can be measured with a graded dose-response curve but not with a quantal dose-response curve.
Spare receptors are said to exist if :
the determination is usually made by comparing the concentration for 50% of maximal effect (EC50) with the concentration for 50% of maximal binding (Kd). If the EC50 is less than the Kd, spare receptors are said to exist
spare receptors Graph
FIGURE 2–3 In a system with spare receptors, the EC50 is lower than the Kd, indicating that to achieve 50% of maximal effect, less than 50% of the receptors must be activated. Explanations for this phenomenon are discussed in the text.
Activity in the absence of ligand is called
constitutive activity
full agonist
In the presence of a full agonist
is a drug capable of fully activating the effector system when it binds to the receptor
In the presence of a full agonist, a partial agonist acts as an inhibitor
Competitive antagonists
Competitive antagonists are drugs that bind to, or very close to, the agonist receptor site in a reversible way without activating the effector system for that receptor
Competitive antagonists increase____
Competitive antagonists increase the ED50; irreversible antagonists do not (unless spare receptors are present).
Agonist dose-response curves graph
Agonist dose-response curves in the presence of competitive and irreversible antagonists. Note the use of a logarithmic scale for drug concentration. A. A competitive antagonist has an effect illustrated by the shift of the agonist curve to the right. B. An irreversible (or noncompetitive) antagonist shifts the agonist curve downward.
Describe the difference between a pharmacologic antagonist and an allosteric inhibitor. How could you differentiate these two experimentally
Allosteric antagonists do not bind to the agonist receptor site; they bind to some other region of the receptor molecule that results in inhibition of the response to agonist . They do not prevent binding of the agonist.
In contrast, pharmacologic antagonists bind to the agonist site and prevent access of the agonist. The difference can be detected experimentally by evaluating competition between the binding of radioisotopically labeled antagonist and the agonist. High concentrations of agonist displace or prevent the binding of a pharmacologic antagonist but not an allo- steric antagonist.
therapeutic index
define & what does it represent
determined from what curve?
The therapeutic index is the ratio of the TD50 (or LD50) to the ED50, determined from quantal dose-response curves.
The therapeutic index represents an estimate of the safety of a drug, because a very safe drug might be expected to have a very large toxic dose and a much smaller effective dose.
Example of Therapeutic Index
For example, in Figure 2–2:
The ED50 is approximately 3 mg, and the LD50 is approximately 150 mg. Therefore the therapeutic index is approximately 150/3, or 50, in mice.
therapeutic window is clinically useful index for ____
The therapeutic window, a more clinically useful index of safety, describes the dosage range between the minimum effective therapeutic concentration or dose, and the minimum toxic concentration or dose
tachyphylaxis
acute drug desensitization
describes an acute, sudden decrease in response to a drug after its administration, i.e. a rapid and short-term onset of drug tolerance. It can occur after an initial dose or after a series of small doses.
Several Mechanisms are responsible for tachyphylaxis
- intracellular molecules may block access of a G protein to the activated receptor molecule
- Second, agonist-bound receptors may be internalized by endocytosis, removing them from further exposure to extracellular molecules. The internalized receptor molecule may then be either reinserted into the membrane (eg, morphine receptors) or degraded
- Third, continuous activation of the receptor-effector system may lead to depletion of some essential substrate required for downstream effects
downregulation
Long-term reductions in receptor number (downregulation) may occur in response to continuous exposure to agonists
upregulation
(upregulation) occurs when receptor activation is blocked for prolonged periods (usually several days) by pharma- cologic antagonists or by denervation.
Graded vs quantal responses
Responses are graded when they increment gradually (eg, heart rate change) as the dose of drug increases
Respones are quantal when they switch from no effect to a specified effect at a certain dose (eg, from arrhythmia to normal sinus rhythm) or if they are measured as positive upon reaching a specified response
Graded vs quantal dose response curves
Graded dose response curves plot the increment in physiologic or biochemical response as dose or concen- tration is increased.
Quantal dose response curves plot the increment in the percent of the population under study that responds with a specified effect as the dose is increased
Efficacy vs potency
Efficacy represents the maximal effect (Emax) of a drug at the highest tolerated dose
Potency reflects the amount of drug (the dose or concentration) required to cause a specific amount of effect, eg, the EC50 for a half-maximal effect. A drug may have high efficacy but low potency or vice versa
Agonism and antagonism
The ability to activate (agonism) or inhibit (antagonism) a biologic system or effect.
Different drugs may have very different effects on a receptor. The effect may be to activate, partially activate, or inhibit the receptor’s function. In addition, the binding of a drug may be at the site that an endogenous ligand binds that receptor, or at a different site
Transmembrane signaling
Many drugs act on intracellular functions but reach their targets in the extracellular space. On reaching the target tissue, some drugs diffuse through the cell membrane and act on intracellular receptors. Most act on receptors on the extracellular face of the cell membrane and modify the intracellular function of those receptors by transmembrane signaling
Receptor regulation
Receptors are in dynamic equilibrium, being synthesized in the interior of the cell, inserted into the cell membranes, sequestered out of the membranes, and degraded at various rates. These changes are noted as upregulation or downregulation of the receptor numbers and usually take days to accomplish. More rapid changes (minutes or hours) in response to agonists may occur as a result of block of access of intracellular coupling molecules to activated receptors, resulting in tachyphylaxis or tolerance
