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94 Cards in this Set
- Front
- Back
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What are the 4 parts of an anesthetic plan?
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anesthesia, analgesia, amnesia, and muscle relaxation
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What is the primary site of action of anesthetics?
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membrane receptors, NOT the lipid bilayer surrounding nerve cells
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What is the primary mechanism of action of inhalation and intravenous anesthetics?
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the potentiation of the inhibitory gamma aminobutyric acid (GABA) receptors
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The recovery from IV anesthesia is described in terms of what? Explain
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a context-sensitive half time; in addition to drug half life, it takes into consideration the duration of anesthetic administration rather than just drug redistribution and elimination profiles
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Why do the elderly show an age related change decrease in drug doses necessary to achieve anesthetic end points?
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a. age-related decline in most receptor populations and an overall decrease in pharmacodynamic responses
b. NOT due to age-related changes in drug pharmacokinetics (i.e. decreased total clearance) |
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Define pharmacology
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the processes by which a drug produces one or more measured physiologic responses
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Define receptor
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a protein or other substance that binds to an endogenous chemical or drug
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What are the three common properties of receptors?
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a. sensitivity (a drug response occurs from a low concentration…)
b. selectivity (…produced by structurally similar chemicals…) c. specificity (…and the response from a given set of receptors is always the same because the cells themselves determine the response) |
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State the bonds, from weakest to strongest, that form between receptors and drugs
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van der Waals < hydrogen < ionic < covalent
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What are the four types of regulatory proteins that are commonly drug receptors?
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a. cell surface proteins
b. enzymes c. carrier molecules (transporters) d. ion channels |
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Where does transduction of a signal to tissue (the increased ion movement into or out of the cell or the activation of a couple G protein) occur in relation to the receptor?
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the receptor and transduction site are the same (previously thought they were just near each other)
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Where are drug receptor proteins located?
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a. within the luminal membrane
b. at the surface of the ionic channel c. a few occupy intracellular sites |
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What are some examples of drugs that act at intracellular receptor sites?
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lidocaine and other amide and ester local anesthetics
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How much of the cell surface of the neuromuscular junction must bind acetylcholine to achieve the tissue response? What does this indicate?
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a. less than 1%
b. this indicates that complete saturation of available receptors with drug molecules is not necessary for a desired tissue response to be elicited |
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What is the time required for a complete circulation?
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a. approx 1 minute
b. during this time, sufficient drug (of IV administration) is delivered to the receptor site for a maximal tissue response, provided an adequate dose was given |
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What is the cause of the delay from initial drug administration to onset of tissue response due to?
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Time required for molecular orientation and attachment to the receptor (aka the time course of the receptor protein conformational change and the tissue response time)
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What is the primary site of IV anesthetic action? What is the exception?
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a. the GABA-A inhibitory receptor channel protein
b.except ketamine |
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What is the primary site of inhalation anesthetic action?
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recent studies suggest they also bind to GABA-A receptor proteins and cause inhibition of signal transduction by increasing the influx of chloride ions through membrane channels
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At minimum, how many configuration points of attachment do individual agonist drugs have? Describe the configuration.
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a. at least three
b. with more points of attachment, a more perfect drug-receptor fit occurs c. agonist drugs can induce receptor proteins to alter their topography to achieve a more exacting fit with the drug d. the alignment of a drug with its receptor is aided by bonding forces, most commonly van der Waals forces or ionic bonding |
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How do volatile anesthetics bond to cell receptors?
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nonspecific hydrophobic bonding mechanism
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What are acceptors?
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a. an alternative drug-binding site on endogenous proteins that reduces the amount of unbound drug available for receptor complexing
b. drugs bound to these proteins are unavailable to interact with receptors, therefore reducing the available drug concentration |
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albumin contains numerous acceptor sites and generally bindS?
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to acidic drugs
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alpha-1 acid glycoprotein and -globulin favor
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basic drugs
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Name some common receptor types
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a. GABA
b. opioid c. 2 d. acetylcholine e. benzodiazepine f. histamine subtypes g. pain-related capsaicin receptor |
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Describe the acetylcholine receptor structure
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a. a pentamer of five peptide subunits conceptually forming a 5-sided ring
b. the central portion serves as the transduction channel c. 2 of 5 subunits are involved in Ach binding; the other three participate in the signal transduction process that involves a protein conformational shift, allowing inward movement of Na+ |
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What other receptor is composed of five peptide subunits forming a pentameric ring?
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GABA-A
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What are the two types of acetylcholine receptors?
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nicotinic and cholinergic
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What does “signal transduction” refer to in the body?
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a. processes by which a cell converts one kind of signal or stimulus into another
b. most of these involved ordered sequences or casades of biochemical reactions inside the cell, referred to as “second messenger pathways” |
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Many of the actions of common anesthetics are transduced through what? Describe
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a. cell surface receptors linked to G protein-coupled receptors (GPCRs)
b. receptor signaling translated to changes to G proteins are then linked to a second messenger such as cAMP or cGMP; these second messengers regulate enzymes such as protein kinases and phosphatases, which drive their ultimate intracellular actions |
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GABA (with chloride ion transduction) and Ach (with sodium ion transduction) have very similar protein compositions but are functionally different; describe why this is.
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the primary difference among drug receptor proteins may be only the selective binding subunits and the ion species moving through the channel; the specific peptide subunits are ultimately responsible for the pharmacologic properties of specificity, affinity and potency
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Describe the drug-induced conformational shift of a receptor
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a. structural shortening of the protein filaments between the inner and outer surfaces, providing an open inner channel that allows the passage of ions through the receptor protein to achieve the intracellular response (like a starfish opening its central mouth)
b. this initiates the dynamics of tissue response |
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What is the drug response equation? Describe
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a. derived from the law of mass action; drug (D) combines with receptor (R) to form a drug receptor complex (DRC) that elicits a tissue response (TR)
b. D + R DRC TR c. the drug receptor complex represents a highly selective process d. yet, the resultant tissue response varies between individuals, reflecting each individual’s receptor and genetic profile, and physiologic state |
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What is the occupancy theory?
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a. the magnitude of a drug’s effect is proportional to the number of receptors occupied
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What do therapeutic drug doses reflect?
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a. average doses of a normal population of individuals
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What influences the pharmacologic response to a drug? 7
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a. age
b. sex c. weight d. body surface area e. basal metabolic rate f. pathologic state g. genetic profile |
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Describe the change in steady-state plasma concentrations of hypnotic drugs as age increases
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a. they decrease (i.e. versed, propofol, MAC) independently of any age effect on drug pharmacokinetics
b. the specifics responsible for this are unknown; suggestions are receptor changes c. associated with aging and kinetic differences in the elderly |
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The theoretical normal distribution of desired (quantal) responses to increasing drug dose takes what shape?
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a Gaussian curve
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Describe the shape of a Gaussian curve in terms of mean, median and mode
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a. the numbers of respondents on both sides of the mean (average dose) are equal
b. the greatest percentage of respondents is near the center of the curve c. the mean, median and mode are equidistant from the two extremes d. atypical respondents fall at each end of the curve e. the mean, median and mode doses are often close but rarely the same in actual dose-response curves |
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Define mean dose
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the arithmetic average of the range of doses that produces a given response
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Define median dose
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the dose on either side of which half of the responses occur
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Define mode dose
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the dose representing the greatest percentage of responses
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What information does the standard deviation (SD) provide?
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population response variability; the actual responses measured and their difference from the calculated mean
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What are the percentages associated with 1, 2 and 3 SDs?
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a. 1 SD: 68% of responses (34% to the right, 34% to the left)
b. 2 SD: 95% of the responses c. 3 SD: 99.7% of the responses |
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A higher SD (3 vs. 1) says what?
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the less the mean reflects the central tendency of responses
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What is the standard error of the mean? Describe
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a. SWM describes variance of the mean; it is equivalent to the SD of the mean
b. by repeating the dose-response measurement on different, normally distributed populations, a slightly different mean dose value is obtained each time because the mean value is only an arithmetic average of the responses obtained |
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Describe how the administration of drugs is determined.
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a. Determined by a mean therapeutic dose per kg of body weight or BSA calculated from a previously determined averaged dose for the normal population
b. this approach may be responsible for overdosing/underdosing of patients, because population variability is not considered in the calculation c. the individual response to a fixed mean dose is frequently less than optimal |
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What is the optimal approach to dosing individual patients?
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IV titration until the desired therapeutic response is achieved
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What are the two types of dose response curves? What do they describe?
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a. graded and quantal
b. describe average drug response and subject variability within a given population |
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Describe the characteristics of the graded dose response curve
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a. plotted in linear fashion
b. characterizes the change in measured response as an administered dose is increased c. hyperbolic shape; greatest change in response occurs to the left on a small portion of the x-axis |
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How does the curve change when plotted on a logarithmic scale?
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a. when plotted on a logarithmic scale, the curve takes an S-shape
b.at the lowest dose, the measure response is small or even nonexistent c. at the highest doses, the response is maximal and approaches a plateau d. between 20% and 80% of the maximal response, the curve approaches a straight line because changes in dose and response reflect a proportional relationship |
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What is the advantage of plotting on a semilogarithmic scale with dose in log units?
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a. provides a more detailed representation of the entire graded dose response curve, especially at the two extremes
b. the potency of different agonist drugs with similar mechanisms of action can be compared c. the ability of an antagonist drug to reduce the response to an agonist can be observed |
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What is the difference between direct and indirect antagonism? Examples
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a. Indirect antagonists do not actually bind to the agonist receptor and are not “true” antagonists
i.e. neostigmine |
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Give an example of chemical antagonism
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a. suggamadex is the only drug in the a new class of muscle relaxant reversals called selective relaxant binding agents – SABA – that encapsulates the relaxant, and the complex is eliminated; this is called chemical antagonism because no direct receptor action is evident
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Describe the characteristics of quantal dose response curves
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a. provides information on the frequency with which a given drug dose produces a desired therapeutic response in a patient population
b. the response is measured in an all-or-nothing fashion c. describes the variation in response to the threshold dose within a population of seemingly similar individuals d. i.e. with propofol induction, a small number of patients become unconscious after admin of 0.5mg/kg, more after admin of 1 mg/kg, and virtually all after 2-3 mg/kg; plotting the cumulative number of patients with all-or-nothing responses over a range of doses produces an S-shaped response curve |
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How does the S-shaped quantal curve differ from the S-shaped graded dose response curve?
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a. the quantal curve reflects population variation for the threshold dose needed to produce a given all-or-nothing desired response
b. the graded curve reflects changes in measured response as an administered dose is increased |
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What descriptive information about population dose response characteristics can be obtained from quantal dose response curves?
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effective dose (ED), toxic dose (TD), lethal dose (LD)
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Describe the therapeutic safety margin equation
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a. therapeutic safety margin = LD1 – ED99/(ED99 x 100)
b. when the therapeutic safety margin is great, the risk of drug-induced death is small, and the margin of safety is wide (the opposite is true when the therapeutic safety margin is small) |
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What is the therapeutic index?
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a. describes a drug’s median therapeutic safety margin for a particular therapeutic effect
b. LD50/ED50 i.e. chemo drugs, volatile anesthetics: have a very narrow margin of safety |
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Describe the median effective dose, often used to compare? Derived from?
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a. ED50 is the dose at which 50% of the population responds as desired
b. it is often used to compare the potency of drugs within a class c. it is derived from the linear portion of the quantal dose response curve (20%-80% of the responders); relatively accurate comparisons of drugs that cause similar responses can be made |
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Briefly state how computer-controlled infusion pumps (Smart Pumps) work
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they use programs based on pharmacokinetic modeling studies in an attempt to approximate the required effect site drug concentration to achieve and maintain a desired level of anesthesia in patients
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What is the drug receptor interaction?
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a. describes the formation of a single drug receptor complex leading to a fractional tissue response (FTR)
b.D + R DR FTR c. the desired tissue response is observed when sufficient receptors have been occupied and activated by free drug d. this process obeys the law of mass action: at steady state, equilibrium exists between bound and unbound drug receptors and the concentration of free unbound drug at the site. |
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What do the terms affinity and efficacy describe?
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a. efficacy aka intrinsic activity
b. describe the degree of drug receptor interaction for a given drug and receptor protein population c. the observed tissue response reflects the quantity of drug receptor complexes intact at any given moment |
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What is the time constant that describes the fractional tissue response after the drug receptor complex formation?
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has been typically considered to be near zero or instantaneous
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What does pharmacokinetic analysis of drug absorption and distribution describe?
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the onset time and magnitude of drug response
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What does drug elimination kinetic analysis describe?
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the duration of the tissue response
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Describe the drug-receptor-response triad
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When a drug combines with its receptor, a conformation change occurs in the receptor protein itself; no tissue response can occur without the structural shift
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What is the two-state model? Agonist and antagonists effects?
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a. states that a receptor is thought to exist in equilibrium between either an activated or inactivated state; constitutively active receptors can exist and are shifted toward the activated state, even though no agonist or ligand is present
b. i.e. receptors for benzos, cannabinoids, serotonin c. agonists shift the equilibrium toward activation d. antagonists freeze the equilibrium e. inverse agonists shift the equilibrium toward inactivation |
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How quickly can the synthesis and destruction of receptor proteins occur?
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a. minutes (rather than days as previously thought)
b. receptor up- and down-regulation can occur during drug infusion, with new receptor proteins being synthesized in a response to availability of unbound free drug |
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Describe pure antagonists
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a. similar in molecular structure to their corresponding agonist drugs
b. however, they are unable to initiate the receptor-protein conformational shift necessary to elicit a tissue response c. these drugs have receptor affinity but lack intrinsic activity/efficacy |
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How does weak vs. strong affinity affect the action of the pure antagonist?
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a. weak affinity: competitive and must be displaced by an agonist (i.e. atropine, esmolol)
b. strong affinity: noncompetitive, usually have covalent bonds, cannot be displaced by agonists (i.e. phenoxybenxamine, aspirin); new receptors must be synthesized if agonist receptor bonding is to occur |
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Antagonists cause what type of shift in the drug dose-response curve?
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rightward, the extent of which reflects the number of available receptors occupied by the antagonist drug
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Describe agonist-antagonist drugs
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they have receptor protein affinity and intrinsic activity, but often only 1/10 to 1/50 the potency of the pure agonist
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What is physiologic antagonism?
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a. involves two agonist drugs that bind to different receptors
b. in competitive antagonism, the drugs bind to the same receptor protein; in physiologic antagonism, both drugs bind to specific unrelated receptor proteins, initiate a conformational shift, and elicit individual tissue responses that generate opposing forces c. i.e. isoproterenol (vasodilate) and norepinephrine (vasoconstrict) d. the drug response that prevails depends on the intrinsic activity of each and on the extent of the tissue response that can be elicited |
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What is chemical antagonism?
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a. occurs when a drug’s action is blocked and no receptor activity is involved
b. i.e. protamine is a positively charged protein that forms an ionic bond with heparin, rendering it inactive c. i.e. suggamadex as well |
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What exerts control of receptors?
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a. regulatory and homeostatic controls like the synthesis and degradation of the receptor by multiple mechanisms; covalent modification; associated with other regulatory proteins; relocation within the cell
b. modulating inputs may come from other receptors, directly or indirectly, and receptors are almost always subject to feedback regulation by their own signaling outputs |
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What is refractoriness?
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a. aka downregulation
b. continued stimulation of cells with agonists results in a state of desensitization, such that the effect that follows continued or subsequent exposure to the same concentration of drug is diminished c. i.e. repeated use of beta-adrenergic bronchodilators for the treatment of asthma; clinically the patient experiences tolerance and higher doses are required to obtain the same effect |
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Chronic administration of an antagonist results in what?
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up-regulation as the number and sensitivity of the receptors increase as a response to chronic blockade; the patient develops tolerance and requires a higher dose of antagonist to counteract the increasing receptor number
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Define drug interaction, what are the 4 types?
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a. an alteration in the therapeutic action of a drug by concurrent administration of other drugs or exogenous substances
b. 4 types: addition, synergism, potentiation, antagonism |
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Define addition
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a. the combined effect of two drugs acting via the same mechanism is equal to that expected by simple addition of their individual actions
b. 1 + 1 = 2 |
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Define synergism
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a. the combined effect of two drugs is greater than the algebraic sum of their individual effects
b. 1 + 1 = 3 |
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Define potentiation
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a. the enhancement of the action of one drug by a second drug that has no detectable action of its own
b. 1 + 0 = 3 |
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Define antagonism
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a. the action of one drug opposes the action of another
b. 1 + 1 = 0 |
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Define ligand
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a. a molecule that is able to bind and form a complex with a receptor to produce a biologic response
b. they are endogenous chemicals such as neurotransmitters and hormones that are exogenously administered drugs |
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Define tachyphylaxis
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a. very rapid development of tolerance with acute drug administration
b. common causes are up- or down-regulation, enzyme induction, depleted NTM, protein conformational changes, or changes in gene expression |
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Define affinity/potency, most potent drug requires the _____ dose?
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a. potency is used to differentiate between different agonists that activate the same receptor and can produce the same maximal response (efficacy) but at differing concentrations
b. the most potent drug requires the lowest dose |
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Define efficacy/intrinsic activity
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a.Efficacy: the ability of a drug to produce the desired response expected by stimulation of a given receptor population
b. refers to the maximum possible effect that can be achieved with the drug |
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What is the spare receptor concept?
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a. The relationship between the number of receptors stimulated and the response is usually nonlinear.
b. A maximal or almost maximal response can be achieved by activation of only a fraction of the receptors present. |
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Recent attention has been focused on this as not only the locus of drug binding but also a primary regulator of the measured pharmacologic response?
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biosphere-the protein receptor site
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What are 2 examples of chemical antagonism/.
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protamine and suggamadex
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What is a partial agonist?
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activates a receptor but cannot produce a maximum response
-may also be referred to as agonist-antagonist |
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What is an inverse agonist?
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a drug or endogenous chemical that binds to a receptor, resulting in the opposite action of an agonist
-prefer to bind to inactivated receptor |
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What receptors up-regulate in the presence of antagonisms and also down-regulate in the presence of agonists?
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Beta-adrenergic receptors
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Ligand-gated ion channels mediate fast?
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synaptic transmission
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G protein- coupled receptors (GPCRs) activate/inhibit?
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adenylyl cylcase, AND activate phospholipase C
-modulate ion channels |
