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Exam 1 - Pharmacokinetics and Dynamics of Anesthesia Drugs

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Question
Answer
What does pharmacokinetics look at?   Mechanisms of absorption and distribution of an administered drug, the chemical changes of the substance in the body.  
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What does pharmacodynamics look at?   Biochemical and physiological effects of drugs on the body, the mechanisms of drug action, and the relationship between drug concentration and effect.  
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What are the ADME properties of a drug?   Absorption, Distribution, Metabolism, Elimination  
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RITO PIE is a mnemonic that lists the routes of administration. What are they?   1) Rectal 2) Inhaled 3) Topical 4) Oral 5) Parenteral 6) IM and SubQ 7) Epidural and subarachnoid  
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What are two ways that drugs can be destroyed before being absorbed?   Enzymes, gastric acid  
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1st pass metabolism is a phenomenon whereby a drug is greatly ________ before it reaches _________.   reduced, systemic circulation  
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What does 1st Pass Metabolism represent?   The fraction of a drug lost during absorption.  
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What vascular system do drugs enter after crossing GI membranes?   Hepatoportal  
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Drugs that are highly metabolized results in _________ extraction ratios.   High  
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What does bioavailability represent?   The amount of PO drug that reaches general systemic circulation.  
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What is the equation for bioavailability?   Amt(oral)/Amt(IV) = (F)Bioavailability  
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What bioavailability would result from a drug that has NO 1st pass effect?   1:1 (oral amt equals the IV amt, 100% of the drug taken made it into systemic circulation)  
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Administration of meds into which portion of the rectum have no 1st pass effect?   Distal 1/3  
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Suppositories inserted into the proximal rectum are absorbed into which veins?   Superior hemorrhoidal veins  
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T/F: A suppository deposited into the lower rectum would have no 1st pass effect.   True  
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Into what veins are high rectal suppositories absorbed into and where are they transported?   Absorption by the superior hemorrhoidal veins and transported to the liver  
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Parenteral meds are delivered directly into what type of circulation?   Systemic circulation  
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Epidural meds are administered into what space?   Outside the dura  
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T/F: Significant volumes of medications can be delivered into the epidural space.   True  
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What 4 areas of medicine benefit from epidural anesthesia?   Orthopedics, GU, general surgery, OB  
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Where are meds delivered into the subarachnoid space placed?   Spinal space  
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What types of medication volumes are administered into the spinal space?   Small  
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How many cc are generally administered w/spinal anesthesia?   2-4  
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What is the volume of CSF in the human body?   ~150ml  
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Drugs delivered into the spinal space have what two types of blockades?   Profound motor and sensory blockades  
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Total volume of medication administered at any one site IM or SQ should be limited to how many ml's?   5ml's  
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Most drug molecules cross tissue membranes by what method?   Diffusion  
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Are lipid bilayers hydrophobic or hydrophilic?   Hydrophobic  
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Hydrophobic drugs have a ________ octanol/H20 coefficient.   High octanol/H20 coefficient  
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Hydrophilic drugs have a ________ octanol/H20 coefficient.   Low octanol/H20 coefficient  
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Where are hydrophobic drugs distributed?   Lipid bilayers of cells  
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Where are hydrophilic drugs distributed?   Hydrophilic compartments such as blood serum  
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What does the octanol/H20 partition coefficient represent?   The ratio of a drug's lipid solubility to H20 solubility at equilibrium  
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What does the octanol/H20 partition coefficient predict?   How well a drug will cross biological membranes.  
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What is the equation for the blood-gas partition coefficient?   Partial pressure of the agent in the blood/partial pressure of the agent in the alveoli (Pa) measured @ equilibrium  
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What does a high blood-gas partition coefficient mean for inhaled anesthetics?   A larger amount of anesthetic is necessary to be dissolved into the blood before equilibrium is reached.  
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What does a low blood-gas partition coefficient mean for inhaled anesthetics?   Minimal amounts of anesthetic is required to be dissolved in blood before equilibrium is reached.  
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Charged particles ________ cross biologic membranes by __________.   Will not, diffusion  
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Molecules of a drug contain what two aspects?   Charged and uncharged molecules.  
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Uncharged particles of a drug means that those portions of the drug are ___________.   Physiologically active.  
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Charged particles of a drug means that those portions of a drug are ___________.   Physiologically inactive.  
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Acidic groups are proton [donors/acceptors].   Donors  
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When does an acidic molecule become charged?   When it donates a proton.  
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Basic groups are proton [donors/acceptors].   Acceptors  
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When does a basic molecule become charged?   After it accepts a proton.  
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What does the Henderson-Hasselbalch equation describe?   The ratio of charged to uncharged molecules at a given pH.  
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What is the Henderson-Hasselbalch?   pH=pKa + [log(base/acid)]  
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The equilibrium between unionized and ionized forms is defined by the ____________.   Acidity constant Ka.  
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Charged particles have what 3 properties?   ionized, water soluble, do not diffuse  
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Uncharged particles have what 3 properties?   non-ionized, lipid solubles, diffuse across cell membranes  
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Why is it that a higher Ka means that there will be a smaller pKa?   Because p represents in the inverse in the equation, or [-log]  
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What does Ka represent?   The strength of an acid solution.  
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What will a high Ka have lots of?   H+ concentrations  
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What is the equation for pH?   [-log H+]  
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Remember pH is represented by the equation [-log H+] therefore as pH decreases, what two conditions occur?   Increased H+ and increased protons  
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What does pKa represent?   The point where a drug exists 50% in the ionized (charged) form and 50% in the non-ionized (uncharged) form.  
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Most local anesthetics are considered to be what types of bases?   Weak bases  
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As a rule, charged particles of a drug will/will not cross biologic membranes by diffusion.   Will not  
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Are charged particles of a drug considered to be ionized or non-ionized?   Ionized  
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Are charged particles of a drug water or lipid soluble?   Water soluble  
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Charged particles of a drug [do/do not] diffuse across cell membranes.   Do not  
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Are uncharged particles considered to be ionized or non-ionized?   Non-ionized  
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Are uncharged particles of a drug water or lipid soluble?   Lipid  
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Do uncharged particles of a drug diffuse across cell membranes?   Yes  
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What is the primary factor that determines onset of action of a local anesthetic?   The pKa  
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A lower pKa means which of the following: 1) increased or decreased tissue penetration 2) shortened or lengthened onset of action 3) increased or decreased lipid solubility   1) increased 2) shortened 3) increased  
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A pKa closer to _______ pH optimizes bilayer penetration.   7.40  
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Inflammation or infection in the extracellular space can _________ the pH.   Decrease  
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A decreased cellular pH may _______ the onset of action of a drug.   slow or delay  
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A basic drug becomes more lipid soluble and less ionized as it exceeds _________ pH.   7.45  
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A weak acid becomes non-ionized and more lipid soluble as it reaches down to _________ pH.   7.35  
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pKa is the point of pH at which the ratio of protonated and non-protonated molecules are __________.   equal  
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A site is mostly non-protonated (non-ionized) if the pH is _________ than the pKa.   Higher  
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A site is mostly protonated (ionized) if the pH is ___________ than the pKa.   Lower  
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What is the primary factor that determines the onset of action?   The pKa  
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What increases tissue penetration and shortens the onset of action: lower or higher pKa?   Lower pKa  
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What must first occur in the oral drug absorption pathway for a medication to be broken down?   Dissolution  
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Acidic drugs are well absorbed in the ________.   Stomach  
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What type of layer coats the small intestine?   Water soluble polysaccharide layer  
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What is the glycocalix?   It is a water soluble polysaccharide layer that coats the epithelial cells of the stomach and limits drug absorption.  
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What is the most important physical property of a drug in relation to ADME?   Lipophilicity  
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Lipophilicity is an important factor in 11 biological and physicochemical properties. Name these properties:   1) Solubility 2) Absorption 3) Plasma protein binding 4) Metabolic clearance 5) Volume of distribution 6) Enzyme/receptor binding 7) Biliary and renal clearance 8) CNS penetration 9) Storage in tissues 10) Bioavailability 11) Toxicity  
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A high Oil-Water Partition Coefficient means that a drug is [hydrophobic/hydrophilic].   Hydrophobic  
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A low Oil-Water Partition Coefficient means that a drug is [hydrophobic/hydrophilic].   Hydrophilic  
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What is the mnemonic rhyme for the bioavailability formula?   Oral over IV equals bioavailability  
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The brain is a fatty tissue, therefore drugs that are __________ are highly absorbed by the brain.   Lipophilic  
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The [ionized/nonionized] portion of a drug molecule has the ability to cross a biologic membrane.   nonionized  
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Most drugs exist in what two conditions?   Weak acids or weak bases  
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There is always a ratio of what two types of molecules?   Charged to uncharged  
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When an acid or base is 50% ionized, what two things are equal?   pH and pKa  
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Is Ka an acid constant or variable?   Constant  
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What does Ka represent?   The strength of an acid solution  
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A high Ka means there is a high concentration of what molecule?   Hydrogen  
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What does "p" represent in the pKa equation   [-log] or the inverse  
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pKa describes the inverse number of what types of molecules in a solution?   Acid molecules  
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The higher the Ka, the [bigger/smaller] the pKa.   smaller  
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Where pH = [-log H+], as H+ (protons) increases, the pH [increases/decreases].   decreases  
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Most local anesthetics exist as [weak/strong] bases.   weak  
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The pKa of lidocaine is 7.9, at a pH of 7.35, lidocaine is mostly [ionized/nonionized].   Ionized  
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What does equilibration, or balanced, mean in anesthesia?   The pKa = pH  
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The closer to equilibration, the _________ the speed of onset of medication.   faster  
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What are three ways that general anesthesia and surgery affect the pharmacokinetics of injected drugs compared to the awake state of injection?   General surgery and blood flow alter: 1)Renal blood flow 2)Hepatic blood flow 3)Hepatic enzyme activity  
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What are two of the more useful means of characterizing the clinical response to a drug?   Context Sensitive Half Time and Effect Site Equilibration  
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Venous drainage from the sublingual veins goes into what vessel?   Superior vena cava  
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What is beneficial about the sustained therapeutic plasma concentrations gained from topical medications?   Prevents the loss of therapeutic effect from peaks and valleys associated with intermittent drug injections.  
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What is the rate limiting step of transdermal administration?   Passage through the stratum corneum (differs individually)  
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What is the duration limit of transdermal application?   7 days  
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When is an acid or a base 50% ionized?   When pH=pKa  
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What are 3 different types of plasma proteins to which molecules can bind to?   albumin, alpha-1 acid glycoprotein, lipoproteins  
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What is the primary plasma protein carrier of acidic drugs in the plasma?   Albumin  
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What is the primary plasma protein carrier of basic drugs in the plasma?   Alpha-1 acid glycoprotein  
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Highly protein bound drugs result in (less/more) available active drug and drug action.   less  
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Warfarin is a highly protein bound drug in plasma. How much of warfarin is protein bound?   99%  
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How does equilibrium reaction and dynamic equilibrium relate to warfarin and protein binding?   Warfarin wants to unbind from a protein as much as it wants to bind to it. Protein therefore acts as a ready reservoir of warfin.  
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What is the definition of enzyme induction?   The increase of enzyme activity by a drug or chemical.  
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Besides the liver, where else can enzyme induction occur?   lungs, kidneys, GI tract  
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Give 1 example of a pharmaceutical medication that causes enzyme induction.   Phenobarbital (barbiturate and anticonvulsant)  
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What are the 4 basic pathways of metabolism?   Oxidation, reduction, hydrolysis, conjugation  
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What is the breakdown of Phase I and Phase II metabolism in relation to the 4 basic pathways of metabolism?   Phase I (oxidation, reduction, hydrolysis), Phase II (conjugation)  
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Hepatic microsomal enzyme activity is low in what patient population?   Neonates, especially premature infants  
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How will a small Vd affect a loading dose?   A small Vd should lead to a small loading dose  
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How will a large Vd affect a loading dose?   A large Vd should lead to a large bolus dose since the drug is diluted amongst a greater amount of tissue  
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What is the most practical measurement for monitoring receptor concentration?   Plasma drug concentration  
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The theory that assumes that the intensity of drug effect is proportional to the number of receptors occupied is called the ______________.   Receptor Occupancy Theory  
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What is the drawback to the Receptor Occupancy Theory?   It does not explain differences in intrinsic effect between drugs that occupy the same number of receptors.  
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True/False: Physiologic agonists produce bodily effects through the same or identical receptor systems.   False – physiologic agonists produce bodily effects through entirely different receptor systems  
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What type of response does a partial agonist create?   A response less than the normal endogenous/exogenous agonist  
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Give an example of a partial agonist   Buprenorphine exerts less opioid effect at the mu receptor than morphine  
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What is the role of an antagonist at a receptor site?   To block or dampen an agonist mediated response  
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T/F: An antagonist provokes a biological response.   False - it serves only to block a response from occurring or to diminish the effect of a response to a stimulus.  
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Most agonists mimic the effects of a/an __________________________ at a receptor.   Endogenous compound  
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When is a ligand or agent considered to be an agonist?   When it produces the desired physiologic effect  
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When does logarithmic increases in response occur in the Dose-Response curve?   When a critical number of receptors have been occupied such that increasing the dose increases the response  
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True/False: Drug molecules move around receptors in a mixture of other molecules in a random fashion.   True – this describes Brownian motion  
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True/False: Drug molecules cannot be removed from a binding site once it has attached to a receptor.   False – most ligands bind only briefly and are then knocked off a receptor by another molecule.  
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What describes how well a particular compound is drawn into and held at the binding site?   Affinity  
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The likelihood that a molecule will interact at a given receptor site is based on the __________________ of that molecule around the receptor site.   Concentration  
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The concept of strength of affinity is based on what two characteristics of a ligand?   It’s shape and chemical structure  
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What does a Dissociation Constant measure?   The propensity of a larger object to separate (dissociate) reversibly into smaller components  
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Affinity constant and dissociation constant are (directly/inversely) related.   Inversely  
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How is optimal pharmacodynamic response achieved?   With good affinity and good intrinsic activity  
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What does intrinsic activity reflect?   The effect a ligand has when it interacts at a receptor  
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What is a ligand?   The substance that interacts at a receptor binding site  
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What is an agonist?   A substance that can bind to a receptor, alter the function of the receptor, and trigger a physiological response  
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True/False: When attached to a cell receptor, an antagonist stimulates a biologic response opposite that of an agonist.   False - Antagonists only prevent or dampen agonist mediated responses by blocking receptors and decreasing the available number of receptors that agonists can bind to  
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What 5 factors affect a drug's Potency?   ADME and affinity  
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What are the two stage of metabolism?   Phase I and Phase II metabolism  
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What is the purpose of Phase I metabolism?   Increase a drug's polarity to prepare it for stage II reactions  
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What is the purpose of Phase II metabolism   Covalently link to drugs or metabolites to render them more water soluble  
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What are two types of Phase I enzymes?   CYP450 and Non-CYP450  
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Where are CYP450 enzymes found?   Smooth endoplasmic reticulum of hepatocytes  
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What does the label P450 represent?   The absorption peak at 450nm when combined with carbon monoxide  
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What types of patients have low microsomal activity?   Newborns and infants  
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Non-CYP450 enzymes are also known as __________.   plasma esterases  
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True/False: Non-P450 enzymes have the ability to go through enzyme induction.   False – Activity of non-P450 enzymes is determined genetically  
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Esterases catalyze drug metabolism primarily through what two means?   Conjugation and hydrolysis  
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Name 4 medications that are metabolized via esterase enzymes.   Succinylcholine, esmolol, remifentanil, procaine  
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Where in the body are esterases found?   Cholinergic neural synapses, RBCs, hepatocytes  
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What are three names for Phase II metabolism?   Synthesis, biotransformation, conjugation  
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What is the most common Phase II reaction?   Glucuronic acid conjugation  
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Give 6 examples of types of Phase II reactions.   1.Glucuronic acid conjugation 2.Glutathione attachment 3)acetylation 4)Sulfate conjugation 4)Glycine conjugation 5)Glutamate conjugation  
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Which type of Phase II reaction results in mercapturic acid derivates   Glutathion attachment  
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What is the suffix that denotes the types of Phase II enzymes?   -transferase  
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What is the difference between esterases and transferases?   Esterases are Non-P450 enzymes that catalyze metabolism in Phase I (i.e. acetylcholinesterase). Transferases are Phase II enzyme that synthesize with molecules in preparation for elimination from the body (i.e. conjugation).  
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What is atypical cholinesterase?   An inherited homozygous-type mutation that results in abnormally slow metabolic degradation of exogenous choline ester drugs such as succinylcholine.  
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What substitution is made in atypical cholinesterase?   A glycine is substituted for an aspartate at the anionic binding site of a protein.  
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What does the glycine for aspartate substitution result in?   The loss of electrostatic interaction necessary for substrate binding.  
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How prevalent is atypical cholinesterase?   Occurs in 1:2500 people  
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Some metabolic enzymes of Phase I is enzymatic in that there can be ____________ or ___________ of enzymes.   Induction or inhibition  
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Phase II enzyme activity is determined by what measure?   genetics  
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What are the three different Phase II enzymes?   Glutathion-S-Transferase, N-Acetyl-Transferase, glucuronosyltransferase  
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What does glucuronosyltransferase catalyze?   The addition of glucuronic acid to substances to render them more water soluble  
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What are three medications that undergo glucuronic acid conjugation?   Midazolam, morphine, propofol  
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What is the function of glutathione-S-transferase   Protect against oxidative stress  
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How does glutathione-S-transferase relate to Compound A?   Compound A nephrotoxicity is attributed to G-S-T dependent activation as occurs with sevoflurane administration  
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What is the function of N-acetyltransferase?   catalyzes the transfer of acetyl groups from acetyl-CoA to arylamines  
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Give an example of an acetyl-type medication that is inactivated by N-acetyltransferase in Phase II metabolism.   Isoniazid  
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Genetic polymorphisms of the N-AT enzyme leads to what two types of conditions?   Fast and slow acetylators  
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The one-compartment model is useful for drugs that (rapidly/slowly) equilibrate with the tissue compartment.   rapidly  
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The two-compartment model is useful for drugs that (rapidly/slowly) equilibrate with the tissue compartment.   slowly  
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What is the point at which the amount of drug administered exactly replaces the amount of drug excreted?   Steady state (rate in=rate out)  
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Besides the equilibrium of intake and output, what else equilibrates with each additional dose of given medication?   The peak and trough of drug concentration  
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When is steady state specifically achieved?   When the peak and trough concentrations are the same after two or more successive doses  
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Steady-state is reached after approximately how many half-lives?   4-5 (textbook states 5, PPT slides say 4-5)  
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What does 1st order rate kinetics describe?   The fractional rate at which a drug is metabolized in a given time period  
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What does 1st order kinetics depend on?   Drug concentration at the site of metabolism and the intrinsic rate of metabolism  
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The fraction of drug metabolized in 1st order kinetics occurs at a _______________ rate.   Logarithmic  
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What does 0 order kinetics describe?   The constant and fixed rate at which a drug is metabolized after the plasma concentration of a drug exceeds the capacity of metabolizing enzymes.  
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True/False: Elimination Half-Time is the time necessary for the body to clear 50% of a drug from tissues and plasma.   False – it is time necessary to decrease plasma drug concentrations by 50%  
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Elimination Half-Time is (directly/indirectly) proportional to Vd.   Directly  
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Elimination Half-Time is (directly/indirectly) proportional to clearance.   Indirectly  
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What is Elimination Half-Life?   Elimination half-life is the time necessary to eliminate 50% of a drug from the (plasma/body) after rapid IV injection.  
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True/False: Elimination half-time and elimination half-life are always equal.   False  
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Half-Life of Effect takes into consideration that the metabolism of parent compounds create ______________, and can still produce physiologic effects.   active metabolites  
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What does “context” refer to in the phrase “context sensitive half-time”?   Context refers to the infusion duration  
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What does context sensitive half time describes the time necessary to eliminated 50% of a drug after _______________.   Discontinuing a continuous infusion of a specific duration  
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Why was CSHT developed?   It was developed due to the limitations of the half-time model  
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CSHT takes into consideration that the distribution of drugs and plasma concentration (are the same/vary) over time.   Vary  
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CSHT is useful in (single/multiple) compartment models.   Multiple  
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What does CSHT take consideration besides infusion duration?   Lipophilicity and metabolism  
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What two factors determine the time to recovery?   The plasma concentration taken when a drug infusion is discontinued and the plasma concentration below which awakening can be expected  
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Time to recovery is (prolonged/shortened) when infusion concentrations are maintained well above levels required to maintain general anesthesia?   Prolonged  
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What describes the delay between the IV administration of a drug and the onset of clinical effects?   Effect-site equilibration  
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Besides the onset of clinical effect, what else does effect-site equilibration reflect?   The time necessary for circulation to deliver a drug to the site of action.  
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The effect site interaction is called the ______________.   Biophase  
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Agents with a rapid onset have a (short/long) effect site equilibrium time.   Short, it doesn’t take long before an effect (or onset) occurs  
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What are 3 medications with a short effect-site equilibration (rapid onset)?   Remifentanil, thiopental, propofol  
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What are 3 medications that exhibit a longer effect-site equilibration time?   Fentanyl, sufentanil, midazolam  
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Failure to recognize __________________ can lead to unnecessary administration of drug.   Effect-Site Equilibration  
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How is Vd calculated?   It is the dose of a drug administered divided by the plasma concentration of drug prior to the beginning of elimination or when steady state has been achieved  
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Binding to plasma proteins and poor lipid solubility leads to a (large/small) calculated Vd.   small  
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What does drug clearance represent?   The volume of plasma entirely cleared of drug per unit of time  
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Total clearance values are calculated by multiplying the _________________________ and __________________________.   Elimination rate constant, volume of distribution  
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To reach steady state infusion what must be equal?   The rate of the infusion must equal the rate of clearance by the liver and the kidneys  
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What is the difference between “side effects” and “toxicities”?   Side effects are usually minor and tolerable. Toxicities are intolerable and potentially life threatening  
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What is the equation for the Therapeutic Index?   Ti = Dtox / Dther  
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What is safer, a drug with a high or a low Ti?   Higher is safer  
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