Fall 2011 - Pharmacology 1 - Test 1 - Pk & Pd

Front 1

What is the goal of therapeutics

Back 1

to obtain a beneficial effect for a sufficiently long period of time with minimal adverse effects

Front 2

the magnitudes of both the desired response and toxicity are fxns of ______

Back 2

the drug concentration at the site of action

Front 3

therapeutic failure results when ______ (2 different situations)

Back 3

concentration is too low (ineffective therapy) or too high (unacceptable toxicity)

Front 4

what is the window between an ineffective (too low) concentration and a toxic (too high) concentration for a drug?

Back 4

the therapeutic window

Front 5

_____ is strongly correlated to the lipid solubility of a drug

Back 5

permeability

Front 6

how is permeability related to the lipid solubility of a drug

Back 6

highly correlated

Front 7

diffusion coefficient of a drug is a fxn of ____


partition coefficient of a drug is ____

Back 7

diffusion coefficient
- fxn of its molecular size, molecular conformation, and solubility in the membrane milieu


partition coefficient
- relative solubility of the compound in lipid and water
- reflects ability of chemical to gain access to the lipid membrane

Front 8

what factor is often manipulated in drug formulations to create different types of absorption vehicles

Back 8

the partition coefficient

Front 9

when will a linear, first order kinetic process be present

Back 9

when the rate of a process is dependent upon a rate constant and a concentration gradient

Front 10

_____ is strongly correlated to the lipid solubility of a drug

Back 10

permeability

Front 11

how is permeability related to the lipid solubility of a drug

Back 11

highly correlated

Front 12

diffusion coefficient of a drug is a fxn of ____


partition coefficient of a drug is ____

Back 12

diffusion coefficient
- fxn of its molecular size, molecular conformation, and solubility in the membrane milieu


partition coefficient
- relative solubility of the compound in lipid and water
- reflects ability of chemical to gain access to the lipid membrane

Front 13

what factor is often manipulated in drug formulations to create different types of absorption vehicles

Back 13

the partition coefficient

Front 14

when will a linear, first order kinetic process be present

Back 14

when the rate of a process is dependent upon a rate constant and a concentration gradient

Front 15

pharmacokinetics involves studying ______

Back 15

the processes of absorption, distribution, metabolism, and excretion

Front 16

pharmacokinetics vs pharmacodynamics

Back 16

pharmacokinetics
- addresses what the animal does to the drug


pharmacodynamics
- addresses what the drug does to the animal

Front 17

what determines how rapidly, at which concentration, and for how long the parent drug will appear in the blood and tissue of the treated animal

Back 17

the pharmacokinetic processes of absorption, distribution, and elimination

Front 18

pharmacodynamic processes determine _____

Back 18

the magnitude of the biological effecct of the drug in a patient at a particular blood or tissue concentration

Front 19

the most impt determinant of the fate of drugs in the body is ______

Back 19

their ability to traverse biological membranes

Front 20

a primary determinant of how easily a drug is absorbed, distributed, and eliminated is _______

Back 20

the drug's inherent lipid solubility

Front 21

if extraction ratio is 1, then clearance is entirely dependent on _______

Back 21

blood flow to the organ

Front 22

in a high extraction ratio drug, what affects clearance _______

Back 22

the blood flow to the organ

Front 23

describe a first-order process

Back 23

the fraction of molecules moving per unit time is constant but the actual amt of molecules being transported changes with time (10% of whatever is left at each given time)

Front 24

the driving force for diffusion is ________


what is it dependent on

Back 24

the concentration gradient across the membrane


dependent upon the dose of drug administered and the water volume of the compartments that the membrane separates

Front 25

describe a zero order process

when does it occur

Back 25

the amt of molecules being transported per unit time is constant no mater what the number of molecules in the system.


takes place after saturation of the transport system occurs

Front 26

the most impt determinant of the fate of drugs in the body is ______________

Back 26

their ability to traverse biological membranes

Front 27

a primary determinant of how easily a drug is absorbed, distributed, and eliminated is _________

Back 27

the drug's inherent lipid solubility

Front 28

a drug's polarity is determined by

Back 28

it's molecular strx and spatial conformation

Front 29

________ molecules tend to cluster together (polar or nonpolar)

Back 29

nonpolar

Front 30

The degree of ionization depends on _________

Back 30

the pKa of the chemical and the pH of the solution

Front 31

________ molecules tend to cluster together (polar or nonpolar)

Back 31

nonpolar

Front 32

the degree of ionization depends on ________ (2 things)

Back 32

the pKa of the chemical & the pH of the solution

Front 33

define pKa

Back 33

the pH at which the drug is 50% ionized and 50% non-ionized

Front 34

acids tend to be transported from _____ solutions and trapped in ______ solutions.

Back 34

transported from acidic soln

trapped in basic soln

Front 35

acids in an acidic solution have more molecules in the _______ form. (ionized/ nonionized)

Back 35

non-ionized

so more able to move

Front 36

what is the purpose of using the Henderson Hasselback equation for acids/bases

Back 36

to calculate the relative proportions of ionized/ nonionized forms of a drug with a given pKa when placed in an aqueous environment at a given pH

Front 37

We have 2 drugs, A & B. Drug A is a nonpolar weak acid witha pKa of 4.2. Drug B is a nonpolar weak base with a pKa of 9.1. Which drug will be more ionized in plasma at a pH of 7.1?

Back 37

initially, both will have higher ionized than unionized fractions in plasma, but which one will be more ionized of the 2?


Drug A:
for an acid pH = pKa + log (ionized/unionized)
so 7.1 = 9.1 + log (i/u)
i/u = antilog (7.1-4.2) or 10^2.9 = 794


for base pH = pKa + log (u/i)
so u/i = 0.01 & i/u = 1/0.01=100

so drug B will be the least ionized of the 2 and more amenable to drug transport across membranes

Front 38

the overall rate of a kinetic process is determined by ______

Back 38

the slowest process involved in its transport

Front 39

what is the rate limiting step for lipid soluble drugs

what about polar drugs

Back 39

blood flow (perfusion limited)
- easily crosses membrane

passage through membrane (permeability limited)

Front 40

in order for a drug to diffuse across a membrane, it must be _______ & _____

Back 40

non-ionized

freely available for diffusion

Front 41

do lipophilic chemicals make good drugs & why

how are they eliminated

Back 41

good drugs
- easily absorbed across GI tract
- will be well distributed throughout the body

liver metabolizes them (biotransformation) to make them more hydrophilic intermediates (metabolites) which are eliminated by the kidney or by excreting them into the biliary tract for GI elimination

Front 42

______ is a carrier mediated process that plays an impt role in the renal and biliary secretion of many drugs and metabolites

Back 42

active transport

Front 43

lipophilic compounds tend to be eliminated by ____.

Back 43

hepatic transformation & biliary or renal excretion

Front 44

lipophilic drugs vs. hydrophilic drugs (how are they absorbed/ distribued/ eliminated/ persistence)

Back 44

lipophilic
- easily absorbed from GI tract
- generally well distributed throughout the body
- eliminated by hepatic biotransformation & biliary or renal excretion
- tend to persist for longer periods of time


hydrophilic (if weak acids or bases)
- absorbed due to pH gradients generated by GI tract
- restricted distribution in the body
- generally eliminated unchanged by the kidney
- shorter residence times in the body

Front 45

2 hallmarks of active carrier-mediated transport

Back 45

specificity & saturability

Front 46

how does the major determinant of transport differ b/w diffusion and carrier mediated transport

Back 46

diffusion
- lipid solubility is the major determinant

carrier-mediated
- the specific nature of the drug/carrier receptor interaction

Front 47

is carrier mediated transport first or zero order

Back 47

initially first order, then zero order once saturated

Front 48

a drug must do what to exert a therapeutic effect

Back 48

get to its site of action at an effective concentration for a sufficient period of time

Front 49

define bioavailability

Back 49

the rate & extent to which a drug enters the systemic circulation unchanged

Front 50

what affects the bioavailabililty of the drug and how does that influence the pharmacological effects?

Back 50

the physicochemical nature of the drug, the formulation of the dosage, and the round of administration affect the bioavailability of the drug and may thereby influence the intensity and duration of pharmacological effects

Front 51

_____ determines which dosage needs to be applied in order to reach adequate concentration in blood and tissues

Back 51

the bioavailability of the drug preparation

Front 52

when can a drug become 100% available

Back 52

when administered IV (except if prodrug)

Front 53

bioequivalence refers to what


what is it looking at

it is based on an estimate of ______ together with ______

Back 53

the comparison made b/w a generic formulation of a drug and a reference dosage form of the drug (generic and name brand)


it looks at whether the generic drug is absorbed at the same rate and extent as in the name brand drug

estimation of relative bioavailability together with a measure of the uncertainty (variance) of the estimate

Front 54

drugs with narrow therapeutic indexes exhibit ______

Back 54

small differences b/w plasma concentrations that are considered therapeutic and toxic

Front 55

the potl for interference with bioavailability is highest with ________ & _______


intermediate with ______, ________, and _______


and lowest with _______

Back 55

highest
- slowly disintegrating compressed tablets
- complicated dosage forms (controlled release, enteric coated, etc.)


intermediate
- suspensions
- tablets
- capsules


lowest
- soln

Front 56

what method of administration achieves the highest concentrations in the shortest period of time & why

Back 56

intravascular administration b/c it bypasses any absorptive phase

Front 57

What form(s) of drug administration are subject to so called "first-pass" hepatic biotransformation

Back 57

enteral

Front 58

one of the main difficulties of enteral administration is ________

Back 58

to get the drug into solution

Front 59

factors affecting oral availability of drugs

Back 59

1. most drugs absorbed by passive diffusion (so solubility important)

2. surface area of the GI mucosa (be thankful you aren't a celiac - and if you are, I feel for you)

3. differential pH of GI tract (pH 1-2 in stomach to 6-8 in SI)
- stomach absorption occurs more with weak acids than weak bases

4. blood flow (absorption from SI is perfusion limited for lipid soluble drugs and permeability rate-limited for polar drugs

5. gastric emptying time and intestinal motility (if you can't figure this out, there is no hope for you)

6. administration of solid dosing forms (drug must be in soln to be absorbed)

7. effect of food (rate and extent of absorption of a drug may increase or decrease in the presence of food depending on preparation

8. misc factors (drug must survive the rumen/ competing chemical rxns/ enterohepatic recycling

9. 1st pass intestinal and hepatic biotransformation

Front 60

place these drugs in order of bioavailability (highest to lowest)

suspension
tablet
solution
capsule
coated tablet

Back 60

soln > suspension > capsule > tablet > coated tablet

Front 61

which way is the best way to go

a. arsenic
b. cyanide
c. atlanto-occipital disarticulation
d. i want to live
e. i don't care as long as i don't have to look at pharm any longer

Back 61

yes

Front 62

advantages and disadvantages of IV administration

Back 62

advantages
- rapid achievement of effective blood concentrations
- precise knowledge of delivered dose
- ability to deliver drus that would cause irritation by other routes

disadvantages
- inability to remove administered dose
- systemic toxicity due to transiently high concentration
- need sterile drug preparations
- drugs insoluble in plasma may cause emboli formation

Front 63

_____ is the primary route for administration of most parenteral drugs

Back 63

IM

Front 64

in what form of administration(s) does the lipid solubility not matter for absorption

Back 64

IM or SQ

b/c both hydrophilic and charged drugs are easily absorbed in the capillary rich networks of muscle tissue

Front 65

what type of drugs are best absorbed across the skin

Back 65

lipophilic drugs

the skin is an excellent barrier to charged molecules

Front 66

drug absorption through the respiratory tract primarily occurs where

Back 66

in the lungs

due to its large surface area, rich blood supply, and exceedingly thin alveolar wall

Front 67

drug distribution is _____

Back 67

the reversible movement of drug b/w blood and tissures or b/w ECF and intracellular compartments

Front 68

what drug properties influence drug distribution

Back 68

1. lipophilicity ****
esp impt in BBB, prostate, testes, joint, placenta/ mammary gland, & ocular compartments

2. ionization
drug must be in its free, non-protein bound, unionized form for diffusion to occur

3. specific tissue affinity

Front 69

______ is the primary determinant of drug distribution to tissues

Back 69

the ability to cross lipid membranes (lipohilicity)

Front 70

a drug must be in what for for diffusion to occur

Back 70

in its free, non-protein bound, unionized form

Front 71

what physiological factors affect drug distribution

Back 71

1. tissue perfusion

2. tissue mass (affects how long it will take for blood/tissue equilibration to occur)

3. blood flow: tissue mass ratio (modify the rate & extent of drug distribution)

4. transcellular fluid compartments

5 tissue specific transport processes (selective transport mechanisms that accumulate compounds against a concentration gradient)

6. plasma and tissue protein binding

Front 72

total blood flow is greatest to ____, _____, _____ and ______ with highest perfusion rates to _____, _____, and _____

would you expect total drug concentration to rise most, or least rapidly in these organs

Back 72

blood flow
- brain
- kidneys
- liver
- muscle

perfusion rates
- brain
- kidney
- liver
- heart


rise most rapidly

Front 73

what are the transcellular fluid compartments (7)

Back 73

cerebrospinal

cochlear/ perilymph

intraocular

pericardial

peritoneal

pleural

synovial

Front 74

name 4 plasma proteins involved in drug binding

Back 74

albumin
- binds neutral and weakly acidic drugs

alpha 1 acidic glycoproteins
- binds basic drugs

high affinity hormone transport proteins
- corticosteroids
- thyroxin
- testosterone

lipoproteins
- very lipophilic compounds (really partitioning, not binding)

Front 75

the volume of distribution is a _________ relating the ______ & ________

Back 75

proportionality constant

relating the concentration of drug in plasma & the administered dose

Front 76

physiologically, what doe svolume of distribution reflect

Back 76

how much dilution occurs when the drug is distributed throughout the body

Front 77

why is Vd referred to as the apparent volume of distribution

Back 77

b/c it wrongly assumes that all drug assayed in the plasma is available for distribution

Front 78

which tissues are demarcatd by specific membrane boundaries and what effect does this have on equilibration

Back 78

- cerebrospinal
- cochlear/ perilymph
- intraocular
- pericardial
- peritoneal
- pleural
- synovial


equlibrium is delayed b/c it must diffuse through additional tissue boundaries

Front 79

what is the final stage of drug disposition


what parameter is used to evaluate the efficiency of the process

Back 79

elimination from the body


clearance

Front 80

define elimination

Back 80

the irreversible removal of drug from an animal

Front 81

does anyone really give a crap about all this $#*t

Back 81

i don't think so

Front 82

elimination can occur by what 2 mechanisms

Back 82

excretion into urine or bile

metabolism to a changed chemical entity

Front 83

clearance can be defined using what 2 independent concepts

Back 83

1. the rate of drug excretion relative to its plasma concentration

2. the volume of blood cleared of a substance by an organ per unit time

Front 84

clearance has units of _____

Back 84

flow (volume/time)

Front 85

a drug enters the liver or kidney at a certain rain tat is dependent on _______ & ________.


the drug leaves the organ at a rate dependent on ____ & _____

Back 85

the concentration of drug in the arterial blood & the organ's blood flow


the concentration of the drug in venous blood & blood flow

Front 86

clearance is simply a fxn of _____


it was first defined as

Back 86

the blood flow to the organ and the efficiency of drug elimination by an organ

the rate of drug excretion relative to its plasma concentration

it is now the extraction ratio

Front 87

clearance is totally dependent on _______

Back 87

the blood flow to an organ

Front 88

what are the levels associated with a drug being labeled highly, intermediate, or low extracted

Back 88

high: 1.0 > E > 0.7
(blood flow dependent)


intermediate: 0.7 > E > 0.3


low: 0.3 > E > 0.01

Front 89

name some physiological factors which affect clearance

Back 89

blood flow

extent of plasma protein binding

organ's enzymatic or secretory activity

Front 90

what physiological factor(s) determine clearance for:

a) for drugs with high extraction ratios


b) drugs with low extraction ratios

Back 90

a) blood flow to the organ


b) some other rate-limiting step causes low extraction ratio
- inadequate quantities of enzymes to metabolize the drug
- poor biliary transport
- poor diffusion of the drug to the site of metabolism
- high degree of plasma protein binding
- RBC partitioning which restricts delivery of drug to the organ

the extent of protein binding and changes in the extent of metabolizing enzyme are both impt factors

Front 91

hepatic biotransformation

phase 1 vs phase 2

Back 91

phase 1
- metbolic rxns add or remove polar groups
- metabolites are directly excreted by biliary or renal processes or provide fxnal groups to which conjugates are added in phase 2 rxns


phase 2
- conjugation rxns couple a parent drug or a metabolite (with an appropriate fxnal group) to a polar endogenous substrate
- products are larger and more polar which restricts their distribution (and thus activity) in the body and allow for biliary or renal excretion/ secretion

Front 92

Why did the chicken cross the playground?

Back 92

To get to the other slide

Front 93

the primary enzyme system responsible for phase 1 oxidative drug biotransformation in the body is the ___________ system


where is it found

Back 93

Cyt P450 MFO system

found in many tissues including liver, kidney, and skin

Front 94

the primary endpoint of drug metabolism is ________

Back 94

the transformation of lipohilic drugs to more polar metabolites which are more easily excreted by the biliary and renal systems

Front 95

biotransformation genrally results in _______


this generally ______ drug effect

Back 95

a metabolite with a reduced pharmocological activity

shortens

Front 96

how do pro-drugs differ in metabolism

Back 96

they are normally inactive and get metabolized to an active form resulting in enhanced activity

Front 97

the process of activating a compound to a toxic metabolite is _________

Back 97

lethal synthesis

Front 98

what factors affect hepatic metabolism

Back 98

induction and inhiition
- one compound induces its own or another's metabolism
- enzyme inhibition decreases the metabolism of a compound
- substrate competition

diet

age

health status

gender

genetics

species differences

saturation

Front 99

the net renal elimination of a drug will be the sum of what

Back 99

glomerular filtration

tubular secretion

tubular reabsorption

Front 100

how is kidney fxn estimated

Back 100

measuring the renal clearances of inulin, creatinine, Cr EDTA, 125 I-iothalamate

Front 101

changes in a drug's protein binding will ______ affect its renal clearance

(not, directly, indirectly)

Back 101

directly

Front 102

1. the 1st step in drug elimination by the kidney is _____


2. the 2nd major component in renal elimination is _____


3. The final determinant of a drug's renal disposition is ______

4. renal excretion of an acidic drug ______ in an acidic urine but _____ in an alkaline urine

Back 102

1. glomerular filtration
- free non-protein bound drugs


2. tubular secretion
- active, carrier mediated process
- saturable


3. the mechanism of nonionic passive tubular reabsorption or back diffusion
- dependent on urine flow rate, lipid solubility of the nonionized drug moiety, and urine pH

5. decreases in acidic & increases in alkaline

Front 103

1. tubular secretion is ____ extraction process (high/low)

2. does protein binding restrict tubular secretion

3. weak acids will be reabsorbed at _____ urinary pH (low/ high)

Back 103

1. high

2. NO b/c the affinity for the transport system is greater than the affinity for the protein (competitive inhibitors can decrease renal excretion)

3. low

Front 104

tubular reabsorption with storage

Back 104

the process whereby some drugs are reabsorbed into the tubules by pinocytosis and stored intracellularly

(drugs such as gentamicin accumulate in teh lysosomes of renal tubular cells causing toxicity and persistent drug residues in the kidney)

Front 105

in what species is bile not stored in the gall bladder

Back 105

horse

rat

me (and Jessica Miner)

Front 106

the elimination of many drugs is dependent upon ______

Back 106

the blood flow to the eliminating organs

Front 107

True or False

In Pennsylvania, no one is allowed to shoot bullfrogs on a Sunday.

In Kingsville, Texas, there is a law against two pigs having sex on the city's airport property

It is illegal for hens to lay eggs before 8 am and after 4 pm in Norfolk, Virginia.

In Texas, it's illegal to put graffiti on someone else's cow.

It is illegal to ride a mule down Lang, Kansas' Main Street in August, unless the animal is wearing a straw hat.

You can't blow your nose in public places in Leahy, Washington, because it might scare a horse and cause it to panic.

Back 107

They are all true

Front 108

pharmacokinetics is the study of


the utility of pharmacokinetic analysis arises from the fact that

Back 108

the time course of absorption, distribution, and elimination of a drug


an analysis of plasma concentrations collected at various post-drug administration reflects the rates of underlying physiological processes involved.

Front 109

What challenges must you address when administering a drug to a patient

Back 109

you have to insure that
- the dose is arge enough to be effective at the site of action
- not too large that toxicity might result
- it is withdrawn at an appropriate time to insure that tissue residues are not present in edible tissues
- and with antimicrobials, the dose must be adequate to minimize the risk of bact resistance emergence

Front 110

in first order systems, the rate of elimination of a drug from plasma is ________ to the amount of drug in plasma


how is this represented mathematically

Back 110

proportional


rate of elimination (mg/hr) = - elimination rate constant x amt of drug in plasma (mg)

Front 111

how do you refer to drug levels in plasma for clinical pharmacokinetics

what does this do for our equation for rate of elimination

Back 111

as drug concentration (mg/L)

rather than amt (mg)

rate of elimination per L of plasma (mg/L/hr) = - elimination rate constant (1/hr) x concentration of drug in plasma (mg/L)

Front 112

in relation to the concentration-time profile (graphically) of a drug in plasma:

1. the rate of drug decay in a system during a small time interval can be expressed by what


2. The slope of the curve would represent what

3. What happens when the Y-axis is converted to logarithmic scale

4. what 2 points define this?

5. The slope represents.

Back 112

1. the slope of the curve during the time interval

2. how much the drug concentration changes

3. the monoexponential curve turns into a straight line

4. the intercept (initial concentration at time 0) and the slope

5. the link between the fundamental first-order differential equation and the 1/2 life of the drug

Front 113

_____ is the pharmacokinetic parameter that ties together clearance and volume of distribution


what other 2 parameters are essential to describing drug kinetics after extravascular administration

Back 113

half-life


systemic availability and absorption rate constant

Front 114

1. As computed, the Vd of a drug refers to

2. Vd is expressed on a _______ basis, thus the Vd achieved is divided by ______

3. How can you calculate the amount of a dose is left in the body at any time if you know the volume of distribution of a drug and the plasma concentration?

Back 114

1. the volume it would occupy at time zero

2. weight basis
divided by the body weight (in kg)

3. amount of drug = Vd x Cp

Front 115

The half life of a drug is dependent on

Back 115

volume of distribution and clearance

Front 116

if something changes volume of distribution, what effect will that have on clearance?

What effect will it have on half life?

Back 116

will not affect clearance

will affect half life

Front 117

in a first order system, 1/2 life is ______ on the dose

(dependent/ independent)

Back 117

independent

Front 118

By ____ half lives, 99.9% of the drug has been removed

Back 118

10

Front 119

By 5 half lives, how much of the drug has been eliminated

Drug concentration ____% of steady state during constant infustion or mult dosing

Back 119

By 5 half-lives, nearly 97% of the drug has been eliminated


By 5 half-lives, drug concentration reaches about 97% of steady-state during constant infusion or multiple dosing

Front 120

define clearance

Back 120

the rate of drug excretion relative to the plasma concentration


the volume of blood cleared of a substance per unit of time

Front 121

what is the rate of drug excretion from the body

Back 121

the administered dose x the fractional elimination rate constant

Front 122

define half life

Back 122

the volume of blood cleared of a substance per unit of time

Front 123

describe half life in a first order process

Back 123

it is a constant value that derives directly from K

T1/2 = 0.693/K

T1/2 = (0.693 x VD) / Cl

Front 124

K =

Back 124

Cl/Vd

Front 125

half life may change if

Back 125

either Vd or Cl, or both change

if both Vd and Cl change in the same direction by the same proportion, half life would not change but peak concentration and AUC would change)

Front 126

if both Vd and Cl change in the same direction by the same proportion what will happen to half life

Back 126

half life would not change but peak concentration and AUC would change

Front 127

if there is a proportional relationship b/w blood and tissue concentrations of a drug, ____ is really useful to describe how long a drug might be effective in the body

Back 127

half life

Front 128

if a drug has a short half life (10 min), how long would it take before the drug would be too low for effect

Back 128

approximately 5 half lives (or 50 min)

Front 129

If a drug has a long half life (24 hours), how long might the drug stay active for

Back 129

5 days

Front 130

_____ is an impt parameter when it comes to constant drug infusion or multiple dose administration

Back 130

half life

Front 131

when a drug is administered by multiple doses, what dosing interval will result in drug accumulation to the plateau range

Back 131

dosing intervals shorter than 3-4 half lives

Front 132

the time to reach steady state is solely dependent upon ______.

Back 132

elimination half life

Front 133

the plasma concentration at steady state will depend on ______

Back 133

the rate of infusion (or administration of mult doses)

the drug clearance (and bioavailability if mult doses given extravascularly)

Front 134

knowledge of _______ and how it might change in sick animals, allows a clinician to select dose intervals that reflect drug kinetics

Back 134

half life

Front 135

in what situation would the dose become a very uncertain measure of drug exposure

Back 135

when individual differences are large and the drug has a narrow safety-efficacy margin

Front 136

what is the importance of AUC

Back 136

with regard to dosage determiniation resides in its relationship with drug clearance that provides a simple way to calculate doses for given AUC targets

AUC = Dose x (F/Cl)

Front 137

define bioavailability

Back 137

the rate and extent of absorption

it has 2 components, systemic availability (F) and rate of absorption

Front 138

what happens with higher values of Ka (absorption rate constant)

Back 138

the peak plasma concentrations are higher and earlier

Front 139

higher systemic availability has what effect on the CT profile

Back 139

they make higer concentration at each time point (the time of peak plasma concentration is unchanged b/c K & Ka are not changed)

Front 140

what is flip flop

Back 140

if Ka is << Kel

(absorption rate constant) << (elimination rate constant)

elimination half life is actually the absorption half life (0.693/Ka)

seen in slow-release formulations

Front 141

_____ & _____ determine the infusion rate (in mass/time)

Back 141

the target steady state concentration and the drug clearance

Front 142

what is the purpose of loading dose

Back 142

to reach a target steady state concentration immediately

Front 143

when does Vd = Volume at steady state = Volume of central compartment

Back 143

in one compartment systems

Front 144

how do you calculate dose when the target is AUC (based on total plasma concentration)

Back 144

calculate based on the relationship b/w AUC and clearance (also F if extravascular)

AUC = dose/Cl

so IV: dose = AUC x Cl

EV: dose = (Cl x AUC) / F

Front 145

How would a physician expect renal impairment to affect dosing of a drug (such as amikacin) and how would they compensate?

Back 145

expect half life to increase but Vd to stay the same

they would select a longer dosing interval to maintain the concentration at the end of the interval within safe levels

in drugs whose peak compensation is not so impt, they may decrease dose to compensate for increased half life

Front 146

a therapeutic window is defined by a specific _______

Back 146

peak and trough plasma concentration

Front 147

when administering a drug in a clinical setting, one may "tweak" the dosage regimen by

Back 147

varying the administered dose or the dosing interval

if both are changed in proportion, the same average plaasma concentration will be maintained, but fluctuations will change accordingly

Front 148

decreased GFR has what effect on half life/ dosing

Back 148

it decreases Cl so it prolongs half life

if normal dosing regimen is used, severe accumulation will result

it is impossible to duplicate the dosing regimen int he normal animal b/c the slope is decreased and the half life is prolonged

you can reduce the dose and give it at normal intervals or give a normal dose at a lengthened interval
- your choice depends on how hte peak concentration relates to both efficacy and toxicity

Front 149

what is the equation for changes in dose or dose interval associated to impaired clearance

Back 149

new dose = old dose x (Cl new/ Cl old)

new dose interval = old dose interval x (Cl old / Cl new)

Front 150

pharmakodynamics deals with

Back 150

what happens to a drug when it gets to its site of action (efficacy or toxicity)

how does a drug exert a biological effect

Front 151

receptors as a mechanism of a drug exerting its effect

Back 151

have at least 2 domains
- binding domain that recognizes drug (ligand)
- effector domain that transfers this binding event inot some action in the cell (signal transduction)

Front 152

drug agonist vs. drug antagonist vs. pure drug antagonist

Back 152

agonist
- mimics the response that an endogenous ligand would produce

antagonist
- one that inhibits the response

pure drug antagonist
- specifically binds to a receptor but produces no signal transduction
- its occupancy of the receptor will prevent the natural ligand from exerting an effect

Front 153

drug effects that are not mediated by cellular receptors (6)

Back 153

1. pH alterations (effect is usually conc dependent)

2. osmotic diureticcs (change ospotic properties of the fluid they are located in)

3. non-specific membrane active agents (such as disinfectants which disrupt phospholipid membranes)

4. interactions with small molecules (EDTA binds to small metal ions allowing their excretion)

5. incorporation of a drug into a macromolecule (the drug serves as a substrate for a synthetic pathway that incorporates it rather than the endogenous compound)

6. Enzyme inhibition

Front 154

pharmacokinetics is useful only if ______

Back 154

there is a relation between drug concentration and biological effect

Front 155

most pharmacodynamic studies are conducted using ______ systems

(in vitro/ in vivo)

Back 155

in vitro

Front 156

when the biological response is measure and plotted against drug concentration a _____ curve results

how is this interpreted

Back 156

hyperbolic dose-response curve

log transformation of concentration data (gives sigmoidal dose-response curve)
- the mid poition of the curve has a linear segment b/w 20-80%

Front 157

drugs that act on the same receptor site can be classified as to their relative ____ & _____

Back 157

potency and efficacy

Front 158

potency vs efficacy

Back 158

potency
- related to the affinity of the drug for the receptor
- lower EC50 = more potent
- defined as the concentration of drug required to produce a certain effect (lower conc = more potent)


efficacy
- the effect seen when 100% of the receptors are occupied
- independent of drug concentration
the maximum effect that a drug can produce

Front 159

lower EC50 = _____ potent

(more/less)

Back 159

more

Front 160

agonists can be classified as

Back 160

full agonists
- 100% maximal efficacy

partial agonists
- < 100% maximal efficacy

Pure antagonist
- zero efficacy

Front 161

in a clinical environment, the most impt property of a drug is

Back 161

efficacy

(for a series of full agonists, potency become simpt since a lower concentration of drug is required for a given level of effect)

Front 162

competitive antagonists

Back 162

reversibly compete for an agonist's occupancy of a receptor site

shifts the dose-response curve is shifted to the right resulting in a greater EC50
(the agonist appears less potent b/c it must compete with the antagonist for receptor occupancy)

Front 163

what happens to the dose response curve and the EC50 in the presence of competitive antagonists

Back 163

it is shifted to the right

increases EC50

Front 164

Non-competitive or irreversible antagonists

Back 164

irreversibly bind to receptor preventing agonist binding

no concentration of agonis may be able to overcome the antagonism if a substantial number of receptors are occupied by non-comp antagonist
- reduces maximal response (efficacy) possible
- EC50 remains the same, but Emax will be lowered

Front 165

in the presence of a non-comp antagonist, the same drug appears to have _____ efficacy but _____ potency

Back 165

lower efficacy but equivalent potency

Front 166

the advantage of a non-competitive antagonist is _______

Back 166

that once the receptor is occupied, the drug need not be present to continue the effect

the duration of action is thus longer (but it is impossible to reverse the block by drug removal)

Front 167

define tolerance

Back 167

the reduction in response to the drug after repeated administration

cross tolerance may occur with pharmacologically related drugs (esp those using the same receptor)

receptor desensitization can also occur (# of receptors is unchanged but efficacy is reduced through altered signal coupling)
- seen with prolonged exposure to B-receptor agonists

Front 168

1. clinical pharmacokinetics is concerned with ______


2. it studies the factors that determine

3. the ideal goal is to

Back 168

1. the rational, safe, and effective use of drugs


2. the time course of the plasma concentration of a drug and its variability

3. to tailor the drug and dosing regiment ot the unique characteristics of each patient

Front 169

linear vs non-linear pharmacokinetics


which has a more difficult dose adjustment

Back 169

linear
- implies direct proportionality between dose and exposure

non-linear
- no proportionality b/w dose & exposure



non-linear

Front 170

clinical pharmacodynamics studies the relationship b/w ______ & ______ or _____ effect

Back 170

drug exposure

pharmacological or toxic effect

Front 171

drug dissplacement from plast protein binding sites by a competing drug is almost always __________

(impt/ unimpt)

Back 171

unimpt

Front 172

How should the exposure parameters of PKPD indices of efficacy be expressed when adjusting the dosage regimen of antimocrobials and why

Back 172

express them in terms of unbound drug

that way they can be extrapolated across species

Front 173

for a single dose, the AUC represents _____

Back 173

the complete exposure of an animal to a drug

Front 174

in the case of antimicrobials administered by mult doses, PK-PD relationships are based on

Back 174

the unbound AUC 0-24, or the area corresponding to a 24 hr dosing interval at steady state

Front 175

what measures of exposure can be relevent for dosage adjustment

Back 175

AUC

dosing intervals <3-4 half lives

measures of exposure related to VD and/or systemic clearance
- peak plasma concentration
- concentration at steady statee after IV constant rate infusion
- the average concentration at steady state after mult doses with constant dose interval
- trough concentration at steady state after mult doses

Front 176

why might some of a drug administered extravascularly not reach systemic circulation

Back 176

poor absorption

drug inactivation in stomach

enzymatic first pass effect

Front 177

define bioavailability

Back 177

the rate and extent of absorption

Front 178

define systemic availability

what does it represent

Back 178

the extent of absorption

represents the frx of the total dose that reaches systemic circulation after extravascular administration and may have a value b/w 0 and 1

Front 179

absolute systemic availability vs relative systemic availability

Back 179

absolute
- determined by comparison b/w dose-adjusted AUCs after IV & extravascular administration


relative
- the same calculation for 2 extravascular administrations (ex PO vs IM)

Front 180

in monogastric spp, what affect does food have on drugs

Back 180

decreases oral availability of dgurs that are not very lipid soluble

increases oral availability of drugs that undergo high first-pass metabolism

may bind certain drugs altering absorption profile

Front 181

in 1st order pharmacokinetic systems, clearance of a drug from plasma is a proportionality constant that relates ______ to _______

Back 181

the rate of elimination (mass/time) to the toal plasma concentration (mass/volume)

Front 182

systemic clearance is defined as

how is it expressed

Back 182

the volume of plasma cleared of drug per unit time

expressed in units of flow (volume/time)

Front 183

__________ is the single most impt pharmacokinetic parameter

Back 183

Clearance

Front 184

What is the single most impt pharmacokinetic parameter & why

Back 184

Clearance

b/c it determines the maintenance dose rate (dose/unit time) required to maintain a given level of drug exposure

Front 185

different animals treated with similar doses will exhibit different AUCs on accound of the biological variability in _____ & ______

Back 185

clearance and systemic availability

Front 186

The AUC of drugs with coefficients of variation (std dev/ avg value) in clearance aboce ____% may be hard to predict in the indiidual patient

Back 186

50%

Front 187

when mult doses are administered at constant dose intervals, the avg conc at steady state is a fxn of

Back 187

the dose rate

systemic availability

clearance

Front 188

The letter of the day is


I'll let you figure out what the letter of tomorrow is....

Back 188

F

Front 189

what happened when the dog went to the flea circus?

Back 189

he stole the show

Front 190

A woman brought a very limp duck into a veterinary surgeon. As she laid her pet on the table, the vet pulled out his stethoscope and listened to the bird's chest.


After a moment or two, the vet shook his head and sadly said, "I'm sorry, your duck has passed away."


The distressed woman wailed, "Are you sure?"
"Yes, I am sure. Your duck is dead," replied the
vet..

"How can you be so sure?" she protested. "I mean you haven't done any testing on him or anything. He might just be in a coma or something."


The vet rolled his eyes, turned around and left the room. He returned a few minutes later with a black Labrador Retriever. As the duck's owner looked on in amazement, the dog stood on his hind legs, put his front paws on the examination table and sniffed the duck from top to bottom. He then looked up at the vet with sad eyes and shook his head.


The vet patted the dog on the head and took it out of the room. A few minutes later he returned with a cat. The cat jumped on the table and also delicately sniffed the bird from head to foot. The cat sat back on its haunches, shook its head, meowed softly and strolled out of the room.


The vet looked at the woman and said, "I'm sorry, but as I said, this is most definitely, 100% certifiably, a dead duck."


The vet turned to his computer terminal, hit a few keys and produced a bill, which he handed to the woman.


The duck's owner, still in shock, took the bill. "£150!" she cried, "£150 just to tell me my duck is dead!"

Back 190

The vet shrugged, "I'm sorry. If you had just taken my word for it, the bill would have been £20, but with the Lab Report and the Cat Scan, it's now £150

Front 191

What is the second most impt pharmacokinetic parameter for dose determination and adjustment

Back 191

Volume of distribution

Front 192

the volume of distribution is a fxn of


it represents


what is it useful for

Back 192

lipid solubility & plasma/ tissue protein binding of the drug

represents the volume tinto which ta drug appears to be distributed with a conc similar to that of plasma

useful for determining loading dose

Front 193

volume of distribution may be very impt for what

Back 193

initial tx of drugs with long half lives

b/c 4 half lives are needed to reach conc in plasma > 90% of the target avg conc at steady state

Front 194

what is the terminal elimination half life

what does it provide an indication of

Back 194

the time it takes for the conc of the drug in plasma at any time to decrease by 1/2


provides an indication of
- the time course of drug elimination (by 4 half lives, the plasma conc of drug will have decreased by 93%)
- the time course of drug accumulation
- the required dose interval, in particular for drugs with pharmacodynamic effects paralleling plasma concentrations

Front 195

the choice of dose interval is affected by

Back 195

the half life
- a hybrid parameter of Vd & Cl

the therapeutic index

the expected level of compliance

Front 196

outcome of infection in animal models has been shown to correlate well with 1 of 3 PKPD parameters, namely ______, _______, & ______

Back 196

the ratio of peak plasma conc of the drug to the minimum inhibitory conc (Cmax/MIC)

the ratio of the 24hr area under the curve to the min inhibitory conc (AUC/MIC)

the frx of the dose interval during which the conc of the drug in plasma remain above the min inhibitory conc (T>MIC)