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Kinetics Exam 1
| Question | Answer |
|---|---|
| The magnitude of response (good or bad) depends on.. | ...concentration of the drug at the site of action. |
| Pharmacokinetics | The quantitative study and characterization of the time course of drug ADME. |
| 3 Tools we use in Pharmakinetics | a. Pictorial and graphical understanding of the shapes of conc.-time profiles b. Mathematical models c. Equations |
| Concentration-time profiles depend on... | ...route of administration and disposition of drug (ADME) |
| A^X x A^Y= | A^(X+Y)...add exponents |
| (a^x)y= | a^(xy)...multiply exponents |
| a^x/a^y= | a^(x-y)...subtract exponents |
| 1/a^x= | a^-x...take inverse of exponent |
| log(b)N= | N=b^x |
| log(10)100=2 | 10^2=100 |
| ln e^-x= | = -x |
| The slope of a curve is equal to: | a. change in y divided by the change in x b. slope (m)= (y2-y1)/(x2-x1) c. rise over run |
| First-order Reactions | a. Amt of A decreases over time at a variable rate b. Rate is greater when conc. is greater c. Rate decreases when A is elminated d. Rate constant = k e. non-log plot is curved f. Natural log is straight line g. half-life is constant; independ of or |
| Units of 1st-order Reactions | hrs-1 |
| Zero-order Reactions | a. Rate of elimination is constant b. large doses take longer to eliminate than small doses c. halflife is variable; dependent on original amt. d. amt of A decreases at constant rate e. Rate is independ of conc. of A f. Nonlog is straight; logged cur |
| Units of Zero-order Reactions | mass/time...mg/min |
| How many half-lifes are neede to be "gone"? | 4-5 half-lives |
| Volume of distribution is a proportionally constant between: | the amount of the drug given and the concentration of the drug in the plasma |
| Permeability is usually increased when the drug is: | a. Small b. lipophilic c. not polar d. not charged |
| Assumptions of the Compartment Model (4) | a. linearity of system (if dose doubles, conc. doubles--> 1st order rxn b. instant distribution w/in compartment c. 1st-order decline in conc. d. homogenous compartments (each compartment the same within the compartment) |
| When a value is multiplied by e^-kt... | the value is reduced (drug decline over time) |
| The y-intercept (where it crosses the y-axis; 1-compartment model)= | Co ...make sure the y-axis is logged |
| The slope (1-compartment model)= | -k (from best fit of line)...make sure y-axis is logged |
| AUC | a. Area Under the Curve |
| AUMC | Area Under the Moment Curve |
| What does Clearance refer to? | Clearance refers to the speed at which a drug is cleared from the body (the volume of a fluid, usually the plasma, that is clear of a drug per unit of time) |
| What are the 2 independent parameters? | Clearance and Volume |
| Name the 2 equations to calculate AUC | 1) Linear Trapezoidal Rule 2) Log Trapezoidal Rule |
| Advantages and Disadvantages of Linear Trapezoidal Rule | Advantage: Simple, can calculate by hand Disadvantage: a. Assumes straight line btw data points b. If curve is steep, error may be large c. Under/Over estimation depends on whether curve is ascending or descending and how much the concentrations ch |
| Advantages and Disadvantages of Log Trapezoidal Rule | Advantages: very accurate for mono-exponential decline and in late time points where interval btw points is substantially increased Disadvantage: may produce large errors on an ascending curve, near the peak, or steeply declining polyexponential curve. |
| Key Points to Remember when calculating AUC | 1) on the ascending side of a triangle, you ALWAYS use the linear rule. 2) on the descending side, there is a debate btw which equation is better (linear or log) |
| Assumptions of Multicompartment Model | a. distribution throughout the system is NOT instantaneous b. Distribution is slower to some compartments (tissues) |
| How can we use 1 compartment math on a multicompartment model? | We simply wait till the distribution phase is completed to start measuring data for calculations. The elimination phase looks the same as the line in a monoexponential decline |
| The distribution phase is the ___ slope. It is ____ and ____ than the beta phase. | alpha; faster and steeper |
| The elimination phase is the ___ slope. It is ____ and ____ than the alpha phase. | beta; slower and shallower |
| During the alpha phase, drug is being removed by ________. | both distribution and elimination. |
| Visually, how can we tell that the graph represents a multicompartment model? | The graph will be bent when logged, so we know it has biexponential decline. |
| What is the purpose of feathering? | Feathering allows for the separation of the distribution and elimination phases. |
| True or False? Subtraction of elimination (beta) phase from the alpha phase enables you to see the distribution phase alone. | True |
| How do you determine when to draw the first measurement to avoid the distribution (alpha) phase? | Multiply the half-life by 4 or 5...This will avoid the distribution phase. |
| In a graph of a multicompartment model, how do you determine A, B, alpha, and beta? | A= y-intercept of alpha line alpha= slope of alpha line B= y-intercept of best fit (beta) line beta= slope of best fit (beta) line |
| Mean Residence Time (MRT)= | the average time that the drug spends in the body |
| What does Vss mean? | Volume of Distribution at Steady-State |
| If V terms are different... | Vbeta > Vss > Vc |
| Sources of Variability in Permeability (4) | a. molecular size b. lipophilicity c. Charge d. Membrane Thickness |
| Permeability is increased with: | a. small drugs b. lipid drugs c. un-ionized (no charge) drugs d. thinner cell membranes |
| Drug Concentration Equilibrium is more rapidly achieved when: | a. drugs are highly permeable b. the membrane has a large surface area c. the compartments from which the drug is moving from and moving into are small |
| Assumptions of Passive Diffusion | a. assumes no competition btw molecules fro absorption b. no saturation |
| Movement of Drugs through a membrane is influence by: | a. Permeability b. Perfusion (blood flow) |
| When is perfusion the rate-limiting step? | a. If membrane offers no barrier, than the rate-limiting step is perfusion. b. At low perfusion rates, perfusion is the rate-limitin b/c there is enough time for a drug to traverse membranes c. At high perfusion rates, PERMEABILITY becomes rate-limiting |
| True or False? Accumulation of drug occurs on the side of the membrane where pH favors greater ionization. | True. |
| Drugs that are weak acids ionize more in _____ environments. | basic/alkaline |
| Drugs that are weak bases ionize more in _____ environments. | acidic |
| The ____ of a drug dictates the degree of ionization at various pH values encountered at sites in the body | pKa |
| Most drugs in _______-soluble form will be reabsorbed by _______ diffusion. | lipid; passive |
| True or False? To increase excretion, change the urinary pH to favor the charged form of the drug. | True |
| Weak acids are excreted faster in _____ pH. The _____ form is favored. | Alkaline/basic.... anion |
| Weak bases are excreted faste in ______ pH. The _____ form is favored. | Acidic....cation |
| What type of drug is capable of passing through membranes and exerting a pharmacological effect? | Unbound drugs (not bound to proteins) |
| What is the rate-limiting step if dissociation of bound drug from binding proteins and diffusion through membranes may occur rapidly? | Perfusion is the rate-limiting step. Alteration in protein-binding usually are not the rate-limiting step in drug movement across membranes. |
| Pros of Oral Route Absorption (3) | Safe, convenient, economical |
| Cons of Oral Route Absorption (6) | a. absorbs slowly b. if drug is insoluble, never enters circulation. c. Absorption variable environment constantly changing d. First-pass metabolism e. May be irritating f. Need patient cooperation. |
| What is the consequence of delaying drug absorption? | a. There will be a variability in drug response b. failure of drug therapy |
| What do absorption characteristics affect? | a. the size of the time-concentration profile b. the shape of the time-conc. profile....Both of these may affect the pharmacological effects |
| True or False? Drugs must be in solution to be absorbed. | True; Therefore, dissolution characteristics can be rate-limiting |
| True or False? Drug absorption can occur in the stomach, small intestines, and large intestines. | True; However, the primary site is the SMALL INTESTINES |
| Why is the small intestines the primary site for drug absorption? | a. absorptive are is huge b/c of microvilli. b. blood flow is approx 1 L/min..that's alot! c. Permeability may be greater than in the stomach. |
| Gastric Emptying is... | ...often a rate-limiting step in absorption. This is b/c emptying prolongs the time it takes for the drug to reach the small intestines (where the majority of absorption occurs) |
| What can slow gastric emptying? | Food, especially fat |
| Why is there less absorption in the large intestines than in the small intestines? | a. Surface area decreases from duodenum to ileocecal junction (btw small and large) b. Junctions btw epithelial cells are tighter in the colon (impedes drug movment, decreases absorption) c. Proteolytic and metabolic enzymes may impact absorption |
| Overall, there is an _____ in pH as you descend the GI tract. | Increase |
| True or False? Drugs must pass through the GI lumen, gut wall, and liver to reach the systemic circulation. | True. |
| 3 Causes of low bioavailability | 1) insufficient absorption time (tends to be a problem for large, polar drugs MW>400) 2) Competing Reactions in the GI Tract 3) Hepatic Extraction (1st Pass Effect) |
| Strategies to Overcome 1st Pass Effect | a. Use a prodrug b. Increase the dose amount c. Use alternate route (buccal or sublingual) |
| What is the rate-limiting step of IM and SubQ Routes? | Perfusion |
| IM and SubQ absorption Facts | a. drugs pass easilyndue to little/no capillary walls impediment. b. small molecules (MW<5,000) may enter capillaries; larger (MW>20,000) enter blood from lymph sys c. Rubbing increases blood flow, temp and injection site cause variability in absorption |
| Pros of Inhalation Absorption Route | a. Rapid onset b. Once drug source removed, no additional drug enters body c. No 1st pass metabolism |
| Cons of Inhalation Absorption | a. Fast can be DANGEROUS b. dosing can be difficult (lung capacity) c. Irritants-->pneumonia d. Not much known about long term effects of particulate matter, may cause damage??? |
| Transdermal Absorption | a. must be lipid soluble b. even, slow rate of absorption c. some cmpds can poison thru skin (malathion) |
| Definition of Distribution | the reversible transfer of drug from one location to another within the body; info on distribution can be obtained by measuring blood concentrations |
| What can limit distribution (2)? | Permeability and Perfusion |
| Perfusion rate-limiting distribution occurs with: | a. small, lipophilic drugs diffusing across membranes b. other drugs (except macromolecules) diffusing across loosely knit membranes (Ex: capillary walls of muscle) |
| Perfusion Rate of Different Body Sites (Largest and smallest rate) | a. Large to small: lungs, kidneys, fat/muscle the same |
| A note on equilibrium | Equilibrium does not mean that there is equal concentrations in different compartments. It means they are in balance (steady state) with each other |
| Fractional rate of exit (kT) | A measure of how rapidly drug would leave the tissue if the arterial blood concentration dropped to 0. |
| Drugs leave high affinity tissues and poorly perfused tissues ________. | Slowly |
| Drug plateau (equilibrium) concentrations will be higher for drugs with _____ Kp values | higher |
| Time to equilibrium and loss of drug from tissue will take longer if: | a. longer half life b. poorer perfusion c. greater partitioning of a drug into tissue |
| Permeability rate-limitations occur with: | a. polar drugs diffusing across tightly knit lipoidal membranes (BBB) |
| Why does penetration into muscles more rapid than into brain tissue? | B/c of the porosity of muscle capillary membranes and if perfusion is the rate limitation |
| Blood Brain Barrier | permeability limitation at the capillary level; limits the penetration of many polar molecules |
| What does a low volume of distribution mean? | Means that the drug is mainly confined to blood and body water |
| What does a high volume of distribution mean? | Means that the drug is widely distributed to tissues |
| The larger the volume of distribution.... | ...the smaller the fraction in plasma |
| Volume of distribution is the sum... | of plasma volume + Volumes of each of the tissues |
| Primary Binding Protein for acidic drugs | albumin |
| Primary Binding Protein for Basic drugs | alpha-1-acid glycoprotein (AAG) |
| Hypoalbuminemia is seen in: | burns, cancers, inflammation, liver diseases, malnutrition, nephrotic syndrome, renal disease, surgery |
| Implications of hypoalbuminemia when dosing a patient | If pt is hypoalbuminemic, and they are using a drug that binds to albumin (drug is acidic), then there will be a low % binding of drug |
| In order for a drug to be pharmacologically active, it must be: | Unbound |
| AAG (alpha-1-acid glycoprotein) | a. is an acute phase reactant (increases under stress) b. binds basic drugs c.normal serum conc= 80mg/dl, but can reach up to 300-400mg/dl under stress |
| 3 ways to separate bound and unbound proteins | 1) super centrifuge 2) dialysis 3) filter (larger/bound from small/unbound) |
| Since fraction unbound (fu) is ______ on the total protein concentration, if protein binding is very high, fu will be proportional to the altered protein concentrations | Dependent |
| The volume of distribution is dependent on: (4) | a. volume in plasma b. volume in tissue c. fraction unbound in plasma d. fraction unbound in tissue |
| The volume of distribution increases when: | a. the fraction of unbound in plasma increase and the fraction unbound in tissue decreases |
| The volume of distribution decreases when: | a. the fraction of unbound in plasma decreases and the fraction of unbound in tissue increases |
| For small molecule drugs that are highly bound in plasma, and not bound in tissues... | ...V (amt of drug in body) is the same as the volume of distribution of plasma proteins (7.5 L) |
| For high MW drugs (MW>70,000) that distribute very slowly to tissues... | V is approximately plasma volume (3L) |
| For drugs not bound in plasma or tissue, the volume can vary between... | that of extracellular fluid (16L) and total body water (42L) |
| Definition of Metabolism (biotransformation) | The enzymatic conversion of drug to metabolite |
| Enzymatic conversion is ____ at a given site, but the drug concentration is ______. | constant, variable |
| If drug conc. is lower than enzyme conc, the process is _____ order and is ______. | First-order; linear |
| If drug conc is high and all of the enzymes are complexed with a drug, the process is ____ order and ______ occurs. | Zero-order; saturation....non-linear |
| Where can metabolism occur? | brain, kidneys, lungs....but MOSTLY in liver!! |
| Metabolism usually results in the formation of: | a more polar metabolite, so that it can be eliminated in the urine |
| Reasons a drug can have a poor bioavailability: | 1) poor absorption 2) efflux back into GI tract 3) First pass effects |
| Liver Extraction ratio (ER) provides: | a direct measurement of drug removal by the liver after oral admin of a drug....ER is usually less than 1 because the conc of drug entering the liver is greater than the conc of drug leaving the liver |
| What happens when metabolism is saturated? | a. Elimination will become non-linear. |
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