RE Chapter 5 Flashcards
Using dose response curves, the actions of drug can be quantified and expressed as the effective dose (ED50), toxic dose (TD50) and lethal dose (LD50). The therapeutic index is is the:
This is known as the _______ drug response:
LD50/ED50
Quantal Drug Response
The number and activity of a receptor population may increase or decrease in response to (usually) chronic drug administration. This is known as:
Receptor adaptation (tolerance)
In biochemistry a molecule that is able to bind and form a complex with a receptor to produce a biologic response.
Ligand
Examples of ligands?
Endogenous chemicals such as neurotransmitters or hormones that are administered exogenously as drugs.
Very rapid development of tolerance, frequently with acute drug administration, is known as _____________.
tachyphylaxis
Common causes of tachyphylaxis:
up or down regulation, enzyme induction, depleted neurotransmitters, protein conformational changes, and changes in gene expression.
According to the space receptor concept- the relationship between the number of receptors stimulated and the response is usually linear or nonlinear?
nonlinear (pg 60)
A maximal response or near maximal response can occur often by activation of only a fraction of the receptors present.
A drug or endogenous chemical that binds to a receptor resulting in the opposite action of the agonist is known as….
Inverse agonist.
A drug or endogenous chemical that activates a receptor but cannot produce a maximum response but may also partially block an agonist is termed
Give an example
A partial agonist or agonist-antagonist.
nalbuphine
What is the difference between the terms efficacy and affinity:
Efficacy is the drugs ability to deliver the desired response and may also be expressed as intrinsic activity relating to its maximum effect. Affinity is based on the drugs potency where the most potent drug requires the lowest dose.
A drug that has affinity for a receptor but no efficacy is termed:
Antagonist.
In general an agonist or antagonist commonly has a higher affinity for a receptor?
Antagonist.
Competitive or noncompetitive antagonists are reversible?
competitive is reversible, noncompetitive is not.
The primary site for of anesthetic action is now considered to be ________, not the lipid bilayer surrounding the nerve cells.
membrane receptors
What is the primary mechanism of action of inhalation and IV anesthetics?
the potentiation of GABA (the inhibitory y-aminobutyric acid receptor)
The recovery time from IV anesthetics is described in terms of….
context sensitive half- time
The difference between context sensitive half-time and drug half-life is:
context sensitive half-time takes into account the duration of anesthetic administration not just the drug redistribution and elimination profiles. (like running a propofol TIVA for 10 hours vs an intubating dose?)
Name the three common properties of receptors:
sensitivity, selectivity, and specificity
List the bonds that form between drug and receptor from weakest to strongest:
(hydrogen, ionic, van der Waals, hydrophobic and covalent)
van der Waals hydrophobic hydrogen ionic covalent
Name the 7 receptor classifications
7-transmembrane receptors Ligand-gated ion channels Ion channels catalytic receptors nuclear receptors transporters enzymes
The GABA-A inhibitory receptor has been implicated and suggested as a primary site of IV anesthetics…except for which drug??
Ketamine
Volatile anesthetics like N2O, des, sevo and iso bond to cell receptors by means of…..covalent, ionic, hydrogen or hydrophobic bonding?
nonspecific hydrophobic bonding mechanisms
Some endogenous proteins, like Albumin, provide alternative drug binding sites known as ___________. What type of drug generally binds here?
acceptors
acidic drugs
How do acceptors affect drug administration?
drugs bound to acceptors are not available to interact with receptors, highly protein bound drugs are therefore less available for active drug concentrations.
_____________ refers to the processes by which a cell converts one kind of signal or stimulus into another.
signal transduction
The signal sequences or cascades achieved by signal transduction are commonly referred to as _________
second messenger pathways
Receptor signaling translates changes to _______________, that are linked to second messengers such as ___________________.
G proteins
cAMP or cGMP
The second messengers regulate enzymes such as ___________ which do what?
protein kinases and phosphatases which drive their ultimate intracellular actions.
Signal transduction for the GABA-a receptor involves inward movement of which ion through the opened central channel….
Sodium, Chloride, K, or Calcium?
chloride
GABA and the chloride ion transduce and inhibitory signal while acetylcholine and what ion produce and excitatory signal?
sodium
For many drugs, the composition of the receptor protein and the signal transduction process may be identical even though the tissue response is not. The primary difference among drug receptor proteins may be only………..
the selective binding subunits and the ion species moving through the channel.
____________ is ultimately responsible for the pharmacologic properties of specificity, affinity, and potency.
the specific peptide subunits
Give some examples of drugs we use that are selective in their receptor binding and thus achieve a better clinical side effect profile.
Precedex, cis, ropivacaine
The drug response equation is derived from which law?
the law of mass action
What is the drug response equation?
D+R <-> (DRC) <-> TR
Drug Receptor Drug/Receptor Complex Tissue Response
Describe the occupancy theory
The magnitude of a drugs effect is proportional to the number of receptors occupied.
In this distribution curve, the mean, median, and mode are equidistant from the 2 extremes.
Gaussian distribution curve
The mean, median, or mode dose is the arithmetic average of the range of doses that produces a given response?
mean dose
What is the median dose?
that dose on either side of which half of the responses occur
What is the mode dose?
the dose representing the greatest percentage of responses.
Name two terms that describe population variability
SD standard deviation and SEM standard error of the mean
The greater the SD, the more or less the mean reflects the central tendency of responses?
the less
The SEM describes…
the variance of the mean. It is equivalent to the SD of the mean.
Name the two types of dose-response curves that describe the average drug response and the subject variability within a given population.
Graded and Quantal
Graded or Quantal- is plotted in a linear fashion and characterizes the change in measured response as an administered dose in increased.
Graded
Which response curve has a hyperbolic shape with the greatest change in response occurring to the LEFT on a small portion of the x-axis?
Graded
Describe the shape of a graded response curve when plotted on a logarithmic scale.
S-shaped
Technically neostigmine is not an antagonist for rocuronium. Why is the term antagonist incorrect in this scenario?
Antagonist drugs that do not bind at the receptor sites of agonists are not actually antagonists. Neostigmine does not compete with Roc at the motor end plate, rather it inhibits acetylcholinesterase which allows Ach to compete at the motor end plate for the receptor leading to muscle tone. It is technically at least a partial form of indirect antagonism.
Which curve provides information on the frequency with which a given drug dose produces a desired therapeutic response within a pt population?
Quantal dose curve
What is unique about the quantal dose curve?
The response is measured in an all or nothing fashion.
what is the equation that represents a drugs safety margin?
safety margin = LD1- ED99/(ED99 x 100)
LD50/ED50 represents what?
the therapeutic index (a drugs median therapeutic safety margin for a particular therapeutic effect)
Another descriptor obtained from the quantal dose-response curve is the ED50 which is….
the median effective dose, the dose at which 50% of a population responds as desired.
The ED50 is derived from which portion of the quantal-dose response curve?
the linear portion
Describe the Two State Model
The receptor is shown in two conformational states-active and resting which exist in equilibrium. When no ligand is present the equilibrium lies far to the left and few receptors are in the active state. Agonists have a higher affinity for the Activated state type receptors so they shift the euqilibrium to the right or activated side.
True or False. The time constant that describes the fractional tissue response after the drug receptor complex formation typically has been considered to be near zero or instantaneous?
True
The phrase ‘pharmacokinetic analysis of a drug absorption and distribution describes the onset time and magnitude of drug response.
Drug elimination kinetic analysis describes what?
the duration of the tissue response.
True or False. When a drug combines with its receptor, a conformational change occurs in the receptor protein itself.
True- no tissue response can occur without the structural shift.
In the two state model explain the action of the agonist, antagonist, and inverse agonist.
Agonist- shifts toward active
Antagonist- freezes equilibrium
Inverse agonist- shift toward inactivation
Receptor upregulation or downregulation can occur over minutes, hours, days, or weeks?
MINUTES! Can occur while an infusion is running in response to the availability of free unbound drug.
Noncompetitive antagonists like phenoxybenzamine and aspirin have a strong affinity for the receptor protein and generally form which type of bond?
covalent and cannot be displaced by the agonist.
On the drug dose response curve….Antagonists cause a rightward or leftward shift? what does that reflect?
rightward shift, the extent of the rightward shift reflects the number of available receptors occupied by the antagonist drug. By comparing the ED50 the curve will show a reduced affinity of the agonist for its receptor when the antagonist is present.
Which simple math equations represents addition, synergism, potentiation, and antagonism.
1+1=3
1+0=3
1+1=2
1+1=0
1+1=2 addition
1+1=3 synergism
1+0=3 potentiation
1+1=0 Antagonism
What is the difference between physiologic antagonism and competitive antagonism?
In competitive the agonist and antagonist are competing for the same site. With physiologic antagonism both drugs bind to specific unrelated receptors and elicit individual tissue responses that oppose each other.
This type of antagonism occurs when a drugs action is blocked and no receptor activity is involved.
Chemical antagonism
Give an example of chemical antagonism, and state why.
protamine and heparin. protamine is a positively charged protein that forms an ionic bond with heparin rendering it inactive. It does not affect the receptors.
Chronic administration of an antagonist results in up regulation or down regulation?
up regulation as the number and sensitivity of the receptors increase as a response to chronic blockade.
Each drug-receptor interaction at the protein receptor elicits a ___________ and the sum of this provides ____________.
a fractional tissue response and the sum of the fractional tissue response provides the observed response
The tissue response continues until when?
the drug dissociates from the receptor.
What is an additive drug effect?
The pharmacological effect of two drugs is the algebraic sum of of the individual drug effects A+B = C+D Drug Effect A C B D
What is a synergistic drug effect?
Two drugs interact to produce a pharmacologic effect that is greater than the sum of the individual effects
A+B> C+D
