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NU 600

Exam 1 - Pharmacokinetics and Dynamics of Anesthesia Drugs

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