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NU 600
Exam 1 - Pharmacokinetics and Dynamics of Anesthesia Drugs
| 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. |
| 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. |
| What are the ADME properties of a drug? | Absorption, Distribution, Metabolism, Elimination |
| 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 |
| What are two ways that drugs can be destroyed before being absorbed? | Enzymes, gastric acid |
| 1st pass metabolism is a phenomenon whereby a drug is greatly ________ before it reaches _________. | reduced, systemic circulation |
| What does 1st Pass Metabolism represent? | The fraction of a drug lost during absorption. |
| What vascular system do drugs enter after crossing GI membranes? | Hepatoportal |
| Drugs that are highly metabolized results in _________ extraction ratios. | High |
| What does bioavailability represent? | The amount of PO drug that reaches general systemic circulation. |
| What is the equation for bioavailability? | Amt(oral)/Amt(IV) = (F)Bioavailability |
| 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) |
| Administration of meds into which portion of the rectum have no 1st pass effect? | Distal 1/3 |
| Suppositories inserted into the proximal rectum are absorbed into which veins? | Superior hemorrhoidal veins |
| T/F: A suppository deposited into the lower rectum would have no 1st pass effect. | True |
| 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 |
| Parenteral meds are delivered directly into what type of circulation? | Systemic circulation |
| Epidural meds are administered into what space? | Outside the dura |
| T/F: Significant volumes of medications can be delivered into the epidural space. | True |
| What 4 areas of medicine benefit from epidural anesthesia? | Orthopedics, GU, general surgery, OB |
| Where are meds delivered into the subarachnoid space placed? | Spinal space |
| What types of medication volumes are administered into the spinal space? | Small |
| How many cc are generally administered w/spinal anesthesia? | 2-4 |
| What is the volume of CSF in the human body? | ~150ml |
| Drugs delivered into the spinal space have what two types of blockades? | Profound motor and sensory blockades |
| Total volume of medication administered at any one site IM or SQ should be limited to how many ml's? | 5ml's |
| Most drug molecules cross tissue membranes by what method? | Diffusion |
| Are lipid bilayers hydrophobic or hydrophilic? | Hydrophobic |
| Hydrophobic drugs have a ________ octanol/H20 coefficient. | High octanol/H20 coefficient |
| Hydrophilic drugs have a ________ octanol/H20 coefficient. | Low octanol/H20 coefficient |
| Where are hydrophobic drugs distributed? | Lipid bilayers of cells |
| Where are hydrophilic drugs distributed? | Hydrophilic compartments such as blood serum |
| What does the octanol/H20 partition coefficient represent? | The ratio of a drug's lipid solubility to H20 solubility at equilibrium |
| What does the octanol/H20 partition coefficient predict? | How well a drug will cross biological membranes. |
| 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 |
| 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. |
| 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. |
| Charged particles ________ cross biologic membranes by __________. | Will not, diffusion |
| Molecules of a drug contain what two aspects? | Charged and uncharged molecules. |
| Uncharged particles of a drug means that those portions of the drug are ___________. | Physiologically active. |
| Charged particles of a drug means that those portions of a drug are ___________. | Physiologically inactive. |
| Acidic groups are proton [donors/acceptors]. | Donors |
| When does an acidic molecule become charged? | When it donates a proton. |
| Basic groups are proton [donors/acceptors]. | Acceptors |
| When does a basic molecule become charged? | After it accepts a proton. |
| What does the Henderson-Hasselbalch equation describe? | The ratio of charged to uncharged molecules at a given pH. |
| What is the Henderson-Hasselbalch? | pH=pKa + [log(base/acid)] |
| The equilibrium between unionized and ionized forms is defined by the ____________. | Acidity constant Ka. |
| Charged particles have what 3 properties? | ionized, water soluble, do not diffuse |
| Uncharged particles have what 3 properties? | non-ionized, lipid solubles, diffuse across cell membranes |
| 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] |
| What does Ka represent? | The strength of an acid solution. |
| What will a high Ka have lots of? | H+ concentrations |
| What is the equation for pH? | [-log H+] |
| Remember pH is represented by the equation [-log H+] therefore as pH decreases, what two conditions occur? | Increased H+ and increased protons |
| What does pKa represent? | The point where a drug exists 50% in the ionized (charged) form and 50% in the non-ionized (uncharged) form. |
| Most local anesthetics are considered to be what types of bases? | Weak bases |
| As a rule, charged particles of a drug will/will not cross biologic membranes by diffusion. | Will not |
| Are charged particles of a drug considered to be ionized or non-ionized? | Ionized |
| Are charged particles of a drug water or lipid soluble? | Water soluble |
| Charged particles of a drug [do/do not] diffuse across cell membranes. | Do not |
| Are uncharged particles considered to be ionized or non-ionized? | Non-ionized |
| Are uncharged particles of a drug water or lipid soluble? | Lipid |
| Do uncharged particles of a drug diffuse across cell membranes? | Yes |
| What is the primary factor that determines onset of action of a local anesthetic? | The pKa |
| 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 |
| A pKa closer to _______ pH optimizes bilayer penetration. | 7.40 |
| Inflammation or infection in the extracellular space can _________ the pH. | Decrease |
| A decreased cellular pH may _______ the onset of action of a drug. | slow or delay |
| A basic drug becomes more lipid soluble and less ionized as it exceeds _________ pH. | 7.45 |
| A weak acid becomes non-ionized and more lipid soluble as it reaches down to _________ pH. | 7.35 |
| pKa is the point of pH at which the ratio of protonated and non-protonated molecules are __________. | equal |
| A site is mostly non-protonated (non-ionized) if the pH is _________ than the pKa. | Higher |
| A site is mostly protonated (ionized) if the pH is ___________ than the pKa. | Lower |
| What is the primary factor that determines the onset of action? | The pKa |
| What increases tissue penetration and shortens the onset of action: lower or higher pKa? | Lower pKa |
| What must first occur in the oral drug absorption pathway for a medication to be broken down? | Dissolution |
| Acidic drugs are well absorbed in the ________. | Stomach |
| What type of layer coats the small intestine? | Water soluble polysaccharide layer |
| What is the glycocalix? | It is a water soluble polysaccharide layer that coats the epithelial cells of the stomach and limits drug absorption. |
| What is the most important physical property of a drug in relation to ADME? | Lipophilicity |
| 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 |
| A high Oil-Water Partition Coefficient means that a drug is [hydrophobic/hydrophilic]. | Hydrophobic |
| A low Oil-Water Partition Coefficient means that a drug is [hydrophobic/hydrophilic]. | Hydrophilic |
| What is the mnemonic rhyme for the bioavailability formula? | Oral over IV equals bioavailability |
| The brain is a fatty tissue, therefore drugs that are __________ are highly absorbed by the brain. | Lipophilic |
| The [ionized/nonionized] portion of a drug molecule has the ability to cross a biologic membrane. | nonionized |
| Most drugs exist in what two conditions? | Weak acids or weak bases |
| There is always a ratio of what two types of molecules? | Charged to uncharged |
| When an acid or base is 50% ionized, what two things are equal? | pH and pKa |
| Is Ka an acid constant or variable? | Constant |
| What does Ka represent? | The strength of an acid solution |
| A high Ka means there is a high concentration of what molecule? | Hydrogen |
| What does "p" represent in the pKa equation | [-log] or the inverse |
| pKa describes the inverse number of what types of molecules in a solution? | Acid molecules |
| The higher the Ka, the [bigger/smaller] the pKa. | smaller |
| Where pH = [-log H+], as H+ (protons) increases, the pH [increases/decreases]. | decreases |
| Most local anesthetics exist as [weak/strong] bases. | weak |
| The pKa of lidocaine is 7.9, at a pH of 7.35, lidocaine is mostly [ionized/nonionized]. | Ionized |
| What does equilibration, or balanced, mean in anesthesia? | The pKa = pH |
| The closer to equilibration, the _________ the speed of onset of medication. | faster |
| 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 |
| What are two of the more useful means of characterizing the clinical response to a drug? | Context Sensitive Half Time and Effect Site Equilibration |
| Venous drainage from the sublingual veins goes into what vessel? | Superior vena cava |
| 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. |
| What is the rate limiting step of transdermal administration? | Passage through the stratum corneum (differs individually) |
| What is the duration limit of transdermal application? | 7 days |
| When is an acid or a base 50% ionized? | When pH=pKa |
| What are 3 different types of plasma proteins to which molecules can bind to? | albumin, alpha-1 acid glycoprotein, lipoproteins |
| What is the primary plasma protein carrier of acidic drugs in the plasma? | Albumin |
| What is the primary plasma protein carrier of basic drugs in the plasma? | Alpha-1 acid glycoprotein |
| Highly protein bound drugs result in (less/more) available active drug and drug action. | less |
| Warfarin is a highly protein bound drug in plasma. How much of warfarin is protein bound? | 99% |
| 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. |
| What is the definition of enzyme induction? | The increase of enzyme activity by a drug or chemical. |
| Besides the liver, where else can enzyme induction occur? | lungs, kidneys, GI tract |
| Give 1 example of a pharmaceutical medication that causes enzyme induction. | Phenobarbital (barbiturate and anticonvulsant) |
| What are the 4 basic pathways of metabolism? | Oxidation, reduction, hydrolysis, conjugation |
| 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) |
| Hepatic microsomal enzyme activity is low in what patient population? | Neonates, especially premature infants |
| How will a small Vd affect a loading dose? | A small Vd should lead to a small loading dose |
| 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 |
| What is the most practical measurement for monitoring receptor concentration? | Plasma drug concentration |
| The theory that assumes that the intensity of drug effect is proportional to the number of receptors occupied is called the ______________. | Receptor Occupancy Theory |
| 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. |
| 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 |
| What type of response does a partial agonist create? | A response less than the normal endogenous/exogenous agonist |
| Give an example of a partial agonist | Buprenorphine exerts less opioid effect at the mu receptor than morphine |
| What is the role of an antagonist at a receptor site? | To block or dampen an agonist mediated response |
| 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. |
| Most agonists mimic the effects of a/an __________________________ at a receptor. | Endogenous compound |
| When is a ligand or agent considered to be an agonist? | When it produces the desired physiologic effect |
| 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 |
| True/False: Drug molecules move around receptors in a mixture of other molecules in a random fashion. | True – this describes Brownian motion |
| 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. |
| What describes how well a particular compound is drawn into and held at the binding site? | Affinity |
| The likelihood that a molecule will interact at a given receptor site is based on the __________________ of that molecule around the receptor site. | Concentration |
| The concept of strength of affinity is based on what two characteristics of a ligand? | It’s shape and chemical structure |
| What does a Dissociation Constant measure? | The propensity of a larger object to separate (dissociate) reversibly into smaller components |
| Affinity constant and dissociation constant are (directly/inversely) related. | Inversely |
| How is optimal pharmacodynamic response achieved? | With good affinity and good intrinsic activity |
| What does intrinsic activity reflect? | The effect a ligand has when it interacts at a receptor |
| What is a ligand? | The substance that interacts at a receptor binding site |
| What is an agonist? | A substance that can bind to a receptor, alter the function of the receptor, and trigger a physiological response |
| 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 |
| What 5 factors affect a drug's Potency? | ADME and affinity |
| What are the two stage of metabolism? | Phase I and Phase II metabolism |
| What is the purpose of Phase I metabolism? | Increase a drug's polarity to prepare it for stage II reactions |
| What is the purpose of Phase II metabolism | Covalently link to drugs or metabolites to render them more water soluble |
| What are two types of Phase I enzymes? | CYP450 and Non-CYP450 |
| Where are CYP450 enzymes found? | Smooth endoplasmic reticulum of hepatocytes |
| What does the label P450 represent? | The absorption peak at 450nm when combined with carbon monoxide |
| What types of patients have low microsomal activity? | Newborns and infants |
| Non-CYP450 enzymes are also known as __________. | plasma esterases |
| True/False: Non-P450 enzymes have the ability to go through enzyme induction. | False – Activity of non-P450 enzymes is determined genetically |
| Esterases catalyze drug metabolism primarily through what two means? | Conjugation and hydrolysis |
| Name 4 medications that are metabolized via esterase enzymes. | Succinylcholine, esmolol, remifentanil, procaine |
| Where in the body are esterases found? | Cholinergic neural synapses, RBCs, hepatocytes |
| What are three names for Phase II metabolism? | Synthesis, biotransformation, conjugation |
| What is the most common Phase II reaction? | Glucuronic acid conjugation |
| 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 |
| Which type of Phase II reaction results in mercapturic acid derivates | Glutathion attachment |
| What is the suffix that denotes the types of Phase II enzymes? | -transferase |
| 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). |
| What is atypical cholinesterase? | An inherited homozygous-type mutation that results in abnormally slow metabolic degradation of exogenous choline ester drugs such as succinylcholine. |
| What substitution is made in atypical cholinesterase? | A glycine is substituted for an aspartate at the anionic binding site of a protein. |
| What does the glycine for aspartate substitution result in? | The loss of electrostatic interaction necessary for substrate binding. |
| How prevalent is atypical cholinesterase? | Occurs in 1:2500 people |
| Some metabolic enzymes of Phase I is enzymatic in that there can be ____________ or ___________ of enzymes. | Induction or inhibition |
| Phase II enzyme activity is determined by what measure? | genetics |
| What are the three different Phase II enzymes? | Glutathion-S-Transferase, N-Acetyl-Transferase, glucuronosyltransferase |
| What does glucuronosyltransferase catalyze? | The addition of glucuronic acid to substances to render them more water soluble |
| What are three medications that undergo glucuronic acid conjugation? | Midazolam, morphine, propofol |
| What is the function of glutathione-S-transferase | Protect against oxidative stress |
| 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 |
| What is the function of N-acetyltransferase? | catalyzes the transfer of acetyl groups from acetyl-CoA to arylamines |
| Give an example of an acetyl-type medication that is inactivated by N-acetyltransferase in Phase II metabolism. | Isoniazid |
| Genetic polymorphisms of the N-AT enzyme leads to what two types of conditions? | Fast and slow acetylators |
| The one-compartment model is useful for drugs that (rapidly/slowly) equilibrate with the tissue compartment. | rapidly |
| The two-compartment model is useful for drugs that (rapidly/slowly) equilibrate with the tissue compartment. | slowly |
| What is the point at which the amount of drug administered exactly replaces the amount of drug excreted? | Steady state (rate in=rate out) |
| Besides the equilibrium of intake and output, what else equilibrates with each additional dose of given medication? | The peak and trough of drug concentration |
| When is steady state specifically achieved? | When the peak and trough concentrations are the same after two or more successive doses |
| Steady-state is reached after approximately how many half-lives? | 4-5 (textbook states 5, PPT slides say 4-5) |
| What does 1st order rate kinetics describe? | The fractional rate at which a drug is metabolized in a given time period |
| What does 1st order kinetics depend on? | Drug concentration at the site of metabolism and the intrinsic rate of metabolism |
| The fraction of drug metabolized in 1st order kinetics occurs at a _______________ rate. | Logarithmic |
| 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. |
| 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% |
| Elimination Half-Time is (directly/indirectly) proportional to Vd. | Directly |
| Elimination Half-Time is (directly/indirectly) proportional to clearance. | Indirectly |
| 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. |
| True/False: Elimination half-time and elimination half-life are always equal. | False |
| Half-Life of Effect takes into consideration that the metabolism of parent compounds create ______________, and can still produce physiologic effects. | active metabolites |
| What does “context” refer to in the phrase “context sensitive half-time”? | Context refers to the infusion duration |
| 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 |
| Why was CSHT developed? | It was developed due to the limitations of the half-time model |
| CSHT takes into consideration that the distribution of drugs and plasma concentration (are the same/vary) over time. | Vary |
| CSHT is useful in (single/multiple) compartment models. | Multiple |
| What does CSHT take consideration besides infusion duration? | Lipophilicity and metabolism |
| 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 |
| Time to recovery is (prolonged/shortened) when infusion concentrations are maintained well above levels required to maintain general anesthesia? | Prolonged |
| What describes the delay between the IV administration of a drug and the onset of clinical effects? | Effect-site equilibration |
| 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. |
| The effect site interaction is called the ______________. | Biophase |
| 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 |
| What are 3 medications with a short effect-site equilibration (rapid onset)? | Remifentanil, thiopental, propofol |
| What are 3 medications that exhibit a longer effect-site equilibration time? | Fentanyl, sufentanil, midazolam |
| Failure to recognize __________________ can lead to unnecessary administration of drug. | Effect-Site Equilibration |
| 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 |
| Binding to plasma proteins and poor lipid solubility leads to a (large/small) calculated Vd. | small |
| What does drug clearance represent? | The volume of plasma entirely cleared of drug per unit of time |
| Total clearance values are calculated by multiplying the _________________________ and __________________________. | Elimination rate constant, volume of distribution |
| 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 |
| What is the difference between “side effects” and “toxicities”? | Side effects are usually minor and tolerable. Toxicities are intolerable and potentially life threatening |
| What is the equation for the Therapeutic Index? | Ti = Dtox / Dther |
| What is safer, a drug with a high or a low Ti? | Higher is safer |
Created by:
philip.truong
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