Pharmacology 4 (Pharmacokinetics)

Front 1

define clearance

Back 1

volume of plasma that would have to be completely freed of drug to account for the elimination

Front 2

how can you determine the total systemic clearance from the clearance of individual organs?

Back 2

clearance by various organs is additive

CLliver + CLkidney + CLother = CLsystemic

Front 3

what is the advantage of using clearance?

Back 3

constant for first-order excretion

Front 4

what are the units for clearance?

Back 4

mL/min (volume/time)

Front 5

what is an extraction ratio?

Back 5

ER = (CA - CV) / CA

CA = arteriolar concentration of drug
CV = venule concentration of drug

Front 6

how can you calculate clearance from extraction ratio?

Back 6

CL = Q x ER

CL = clearance
Q = blood flow
ER = extraction ratio

Front 7

what is the equation for renal clearance of a drug?

what is the disadvantage of this equation?

Back 7

CLkidney = [urine] x (VOL/time) / [plasma]

not useful clinically

Front 8

describe inulin

Back 8

exogenous
freely filtered
not reabsorbed
CL = GFR

Front 9

what is indicated if CLin > CLdrug?

give an example

Back 9

drug is reabsorbed

glucose

Front 10

what is indicated if CLin < CL drug?

give an example

Back 10

drug is secreted

PAH

Front 11

define dosing rate

Back 11

denotes the amount of drug reaching the systemic circulation per amount of time

how much is being given, how often

Front 12

assuming complete bioavailability (f=1), when will steady state for a drug be achieved?

Back 12

when the rate of drug elimination equals the rate of drug administration

Front 13

what is the equation for steady state?

Back 13

f x Dosing Rate = CL x [drug]ss

f = bioavailability (1 for complete bioavailability)
CL = clearance
[drug]ss = concentration of drug at steady state

Front 14

what term is synonymous with steady state?

Back 14

plateau

Front 15

what is the equation for Dosing Rate?

Back 15

f x Dose / Dosing Interval

Front 16

important equation at steady state, substituting dosing rate into steady state equation

Back 16

f x Dose / dosing interval = CL x [drug]ss

f = bioavailability (1 for complete bioavailability)
CL = clearance
[drug]ss = concentration of drug at steady state

Front 17

when is it difficult to achieve steady state quickly?

Back 17

when the drug of interest has a long half-life

Front 18

how is steady state achieved quickly for those drugs that have a long half-life?

Back 18

give one/two priming or loading doses

the priming or loading dose(s) are large doses to get the plasma concentration up to steady state and then maintenance dosing is started

Front 19

how do you calculate the priming dose for a drug?

Back 19

f x loading dose = Vd x [drug]plasma

f = bioavailability (1 for complete bioavailability)
Vd = volume of distribution
[drug]plasma = desired plasma concentration of the drug

Front 20

what phrase is synonymous with fluctuation of drug concentrations?

Back 20

peak-trough difference

Front 21

what is the equation for calculating the drug level fluctuation?

Back 21

ln [M] / [Mo] = -ke x t

[M] = trough concentration
[Mo] = peak concentration
ke = elimination constant = CL / Vd
t = time between doses
CL = clearance
Vd = volume of distribution

Front 22

for a drug, how do you calculate the time it takes to fluctuate 50% of peak concentration? 25%? 10%?

Back 22

t1/2 = 0.693 / ke (trough conc. is 50% that of peak)

t1/4 = 0.29 / ke (trough conc. is 75% that of peak)

t1/10 = 0.11 / ke (trough conc. is 90% that of peak)

Front 23

what is a normal value for glomerular filtration rate (GFR)?

Back 23

125 mL/min

Front 24

how does impaired liver function affect drug elimination?

Back 24

cannot accurately predict which drugs will have prolonged elimination half-lives

cannot accurately predict the extent to which the elimination t1/2 for a drug will be prolonged

Front 25

how do you account for liver function impairment in dosing medications?

Back 25

start with low doses and work the dosage up until therapeutic results are achieved

switch to a drug with solely renal excretion

Front 26

how does renal impairment affect drug elimination of renally-excreted drugs?

Back 26

can predict (somewhat) accurately which drugs will have prolonged elimination half-lives

can accurately predict the extent to which the elimination half-life will be lengthened

elimination half-life for drugs excreted largely by the kidney correlates directly with GFR

Front 27

what is creatinine used for?

Back 27

endogenous substance used to measure GFR

Front 28

where is creatine synthesized?

Back 28

liver

Front 29

how is creatine distributed to the brain and muscle?

Back 29

via the blood as phosphocreatine (source of high energy phosphate in cardiac and skeletal muscle)

Front 30

what is the function of creatine kinase?

Back 30

convert phosphocreatine to creatine as phosphate is used for energy in cardiac and skeletal muscle

Front 31

what happens to creatine after skeletal muscle has utilized its phosphate?

Back 31

diffuses into serum, where it is rapidly converted to creatinine

Front 32

how is creatinine eliminated?

Back 32

primarily by the kidney, almost solely by glomerular filtration

(hence it can be used as an estimate of GFR)

Front 33

what is the equation for estimating the renal clearance of creatinine in males?

Back 33

(140-age)(weight) / (72)(SrCrss)

age in years
weight in kg
SrCrss = serum creatinine in mg/dL (must be at steady state)

Front 34

what is the equation for estimating the renal clearance of creatinine in females?

Back 34

(0.85)(140-age)(weight) / (72)(SrCrss)

age in years
weight in kg
SrCrss = serum creatinine in mg/dL (must be at steady state)

Front 35

what are the two important factors to consider when using the equations which estimate creatinine clearance via plasma creatinine concentration?

Back 35

1) serum creatinine must be at steady state

2) the weight used reflects normal muscle mass, so ideal body weight must be used for obese individuals

Front 36

how do you calculate ideal body weight for males?

Back 36

= 50 + (2.3)(height in inches > 60)

Front 37

how do you calculate ideal body weight for females?

Back 37

= 45 + (2.3)( height in inches > 60)

Front 38

what two actions can be taken to avoid toxicity and to save money?

Back 38

decrease dose

increase interval

Front 39

how does fraction of drug excreted by the kidney affect the half life?

Back 39

drugs that are eliminated primarily by the liver will not have a significant change in half-life even with removal of the kidney

drugs that are eliminated primarily by the kidneys will have a very significant change with damage to or removal of the kidneys

drugs with partial excretion via kidney and partial excretion via liver will change according to what fraction is excreted via kidney when kidney is lost or destroyed

Front 40

why is there greater variation in response to many drugs in the elderly than in younger adults?

Back 40

the threshold for side effects is often lowered in elderly patients

Front 41

what is the pharmacodynamic phenomena that must be considered in the elderly?

Back 41

for many drugs, a given concentration at an effector site produces a greater pharmacologic response in elderly persons than younger persons

more sensitive to drug's effects

Front 42

what are the five pharmacokinetic phenomena that must be considered in the elderly?

Back 42

1) absorption of drugs by GI tract is not usually reduced in elderly

2) serum albumin levels are lower, therefore binding of drugs is reduced and free fraction is increased

3) decline in lean body mass and increase in adipose tissue mass in relation to total body weight in elderly affects drug distribution

4) renal clearance declines in proportion to reduced glomerular filtration

5) changes in liver clearance are difficult to predict

Front 43

how does age affect the drug distribution of a hydrophobic drug?

Back 43

as a patient's age increases, muscle is replaced by fat

a hydrophobic drug will distribute into the extra fat very well, so the volume of distribution increases

Front 44

how does age affect the volume of distribution of a hydrophilic drug?

Back 44

as a patient's age increases, muscle is replaced by fat

a hydrophilic drug will avoid the fat, therefore the volume of distribution will be decreased in elderly patients

Front 45

what is the best measuring tool for determining the ability of an elderly patient to eliminate a drug?

Back 45

clearance

NOT half-life

Front 46

how is dose-response data usually expressed?

Back 46

plotting drug effect vs. logarithm of dose

Front 47

an increase in potency accounts for what type of shift in a drug effect vs. logarithm of dose curve?

Back 47

right shift

Front 48

a decrease in potency accounts for what type of shift in a drug effect vs. logarithm of dose curve?

Back 48

left shift

Front 49

to what does potency relate?

Back 49

affinity of drug for receptor

Front 50

an increase in efficacy accounts for what type of change in a drug effect vs. logarithm of dose curve?

Back 50

expansion up

Front 51

a decrease in efficacy accounts for what type of change in a drug effect vs. logarithm of dose curve?

Back 51

compression down

Front 52

to what does efficacy relate?

Back 52

ability of drug to stimulate receptor

sometimes termed "intrinsic activity" of the drug

Front 53

what type of antagonists are the most common

Back 53

competitive

Front 54

what is a competitive antagonist?

Back 54

an antagonist that binds reversibly at the receptor site, inhibiting the natural ligand from binding

Front 55

how is competitive inhibition overcome?

Back 55

increasing the concentration of the agonist, ultimately achiving the same effect

Front 56

what is the effect of a competitive inhibitor on potency? on efficacy?

Back 56

potency - decreases

efficacy - unchanged

Front 57

what is a noncompetitive antagonist?

Back 57

antagonist that prevents the agonist from producing its effect at a given receptor site by blockading agonist binding or blockading events downstream of receptor stimulation

Front 58

what is the effect of a noncompetitive inhibitor on potency? on efficacy?

Back 58

potency - unchanged

efficacy - decreases

Front 59

describe the change in a Lineweaver-Burk plot for a noncompetitive antagonist

Back 59

shifts left

x-intercept decreases (more negative)

y-intercept increases

**causes a decrease in max effect**

Front 60

describe the change in a Lineweaver-Burk plot for a competitive antagonist

Back 60

line doesn't shift (rotates CCW)

x-intercept increases (less negative)

y-intercept is unchanged

**causes no change in max effect**

Front 61

what are the dependent and independent variables on a Lineweaver-Burk plot?

Back 61

dependent - 1/effect

independent - 1/Dose

Front 62

what are the x- and y-intercepts on a Lineweaver-Burk plot?

Back 62

x-intercept = - 1/KD

y-intercept = 1/Max Effect

KD - drug concentration at which half of the drug is bound

Front 63

what is a partial agonist?

Back 63

molecule which binds to a receptor and produces a lower maximal response than a full agonist

binds and produces a response, but not the strongest response

Front 64

in a log dose v. response curve, what is the effect of a partial agonist?

Back 64

compresses curve down

efficacy is decreased;
potency can be greater, equal or less than a full agonist

Front 65

how are partial agonists explained?

Back 65

receptors are in equilibrium between an active (Ra) and an inactive (Ri) form

drugs alter the equilibrium rather than stimulating receptors

partial agonists have a weaker affinity (preferential binding) for Ra than do full agonists, so it produces a weaker biological response than full agonists

Front 66

how does a full agonist affect receptor equilibrium?

Back 66

has a strong preferential binding for Ra (active form), which drives the equilibrium toward the active form (Le Chatelier's principle), and leads to a stong biological response

Front 67

what is the chemical equation for the explanation of full and partial agonists?

Back 67

D:Ri <-> Ri <--> Ra <-> Ra:D

D - drug
Ri - inactive form of receptor
Ra - active form of receptor

Front 68

how does a partial agonist affect receptor equilibrium?

Back 68

has a slight/weak preferential binding for Ra (active form), which drives the equilibrium toward the active form (Le Chatelier's principle) only slightly/weakly, and leads to a weak biological response

Front 69

how does a blocker affect receptor equilibrium?

Back 69

binds to either Ra (active) or Ri (inactive) with similar affinity which leads to no change in the system's equilibrium

antagonism when a full agonist is present

Front 70

what happens when a drug binds preferentially to the inactive form of a receptor?

Back 70

may further inhibit the system, but will be difficult to see since Ri is already the dominant form

Front 71

for receptor equilibrium, give the equation and tell what is the dominant form under equilibrium conditions (no drugs present)

Back 71

D:Ri <-> Ri <--> Ra <-> D:Ra

D = drug
Ri = inactive form of receptor
Ra = active form of receptor

inactive form of receptor is dominant when no drugs are present, but equilibrium is changed with addition of drugs

Front 72

what type of antagonist is a partial agonist considered to be?

Back 72

competitive antagonist

decreased potency of full agonist when partial agonist is added, but efficacy remains the same

Front 73

what are "spare rceptors"?

Back 73

if the maximal activity of a drug can be reached before all of the receptors are saturated, some receptors remain empty and these receptors are known as spare receptors

Front 74

if there are 100 receptors for a drug and 70 of them are bound at maximal drug effect, how many spare receptors are there?

Back 74

30 spare receptors

spare receptors = total receptors - receptors bound at maximal effect

Front 75

how are spare receptors usually exemplified experimentally?

Back 75

for low-moderate concentrations of antagonist, appears as competitive inhibition (same efficacy, decreased potency), but once the antagonist concentration reaches a point where it saturates enough receptors that there aren't enough to reach maximal effect, the agonist loses efficacy

Front 76

what is the advantage of spare receptors?

Back 76

increased sensitivity to low concentrations of receptor agonist

Front 77

if a drug's concentration is sufficient to bind 25% of available receptors, and there are three intracellular effector molecules, what will be the percent of Emax when there are four receptors?

Back 77

33%

though there are more receptors than effectors (one spare receptor), only 1/4 of the receptors is bound to agonist and binds the effector molecule

1/3 effectors working = 33% of Emax

Front 78

if a drug's concentration is sufficient to bind 25% of available receptors, and there are three intracellular effector molecules, what will be the percent of Emax when there are sixteen receptors?

Back 78

100%

4/16 receptors are bound to agonist, but only three receptors can bind to effector molecules since there are only three effector molecules (16 receptors - 3 effectors = 13 spare receptors)

0.25 x 16 = 4 receptors bound by agonist

Front 79

if a drug's concentration is sufficient to bind 25% of available receptors, and there are three intracellular effector molecules, what will be the percent of Emax when there are twenty receptors?

Back 79

0.25 x 20 = 5 receptors bound by agonist

only 3 effector molecules

therefore, 100% Emax with 17 spare receptors

Front 80

if a drug's concentration is sufficient to bind 25% of available receptors, and there are three intracellular effector molecules, what will be the percent of Emax when there are eight receptors?

Back 80

0.25 x 8 = 2 receptors bound by agonist

2/3 effector molecules utilized

66% Emax with five spare receptors (8 receptors - 3 effector molecules = 5 spare receptors)

Front 81

what are the independent and dependent variables in a quantal log dose-response curve?

Back 81

independent - dose (mg)

dependent - number responding (NOT magnitude of effect)

Front 82

what is ED50?

Back 82

effective dose in 50% of subjects

Front 83

what is LD50?

Back 83

lethal dose in 50% of subjects

(NOT 50% of lethal dose)

Front 84

how is therapeutic index calculated? how is it more commonly seen in clinical settings?

Back 84

TI = LD50 / ED50

given in qualitative fashion (e.g. wide therapeutic window) because the numerical therapeutic index is not clinically useful

Front 85

why are barbiturates dangerous?

Back 85

a moderate dose puts a person to sleep (hypnosis) but just giving a little more can cause them to stop breathing

Front 86

what are the major types of drug receptors?

Back 86

ligand-gated ion channels

G-protein coupled receptors

transmembrane receptors with enzymatic cytosolic domains

steroid receptors

Front 87

what is the most famous ligand-gated ion channel?

Back 87

ligand-gated nicotinic acetylcholine receptor

Front 88

how does the nicotinic acetylcholine receptor function?

Back 88

the receptor forms a transmembrane channel, that permits the passage of Na from outside the cell in only when ACh is bound to the receptor; when this happens the cell is depolarized

(ligand-gated ion channel)

Front 89

how does the GABA-subA receptor function?

Back 89

receptor forms a transmembrane channel, that permits the passage of Cl from outside the cell in only when GABA is bound to the receptor; when this happens the cell is hyperpolarized

(ligand-gated ion channel)

Front 90

what is the most common type of receptor?

Back 90

G-protein coupled receptor

Front 91

describe the G-protein in the resting state

Back 91

alpha and beta:gamma subunits are associated with one another, and GDP is bound to the alpha subunit

Front 92

what causes the exchange of GTP for GDP on the alpha subunit of a G protein?

Back 92

binding of an extracellular ligand (agonist) to a Gprotein-coupled receptor

Front 93

what happens to a G protein after GTP is exchanged for GDP on the alpha subunit?

Back 93

the beta:gamma subunit dissociates from the alpha subunit and the alpha subunit (bound to GTP) diffuses to interact with effector proteins

Front 94

how is GTP hydrolysed to GDP in G proteins?

Back 94

alpha subunit has intrinsic GTPase activity, which leads to hydrolysis of GTP to GDP

Front 95

what causes reassociation of the subunits of a G protein?

Back 95

alpha subunit intrinsic GTPase activity hydrolyses GTP to GDP and the subunits reassociate, so that the cycle can start again

Front 96

in the heart, what is the effect of epinephrine binding to its G protein-coupled receptor?

Back 96

alpha subunit of G protein activates adenylyl cyclase, which catalyzes the conversion of ATP to cAMP, which activates PKA, which causes protein phosphorylation, which increases heart rate

Front 97

in the vascular smooth muscle, what is the effect of epinephrine binding to its G protein-coupled receptor?

Back 97

alpha subunit of G protein activates PLC, which catalyzes conversion of PIP2 to DAG and IP3

IP3 stimulates release of Ca from the ER

DAG activates PKC, which works with Ca to phosphorylate proteins, which causes vascular smooth muscle contraction, which increases total peripheral resistance

Front 98

how are different alpha subunits of G protein-coupled receptors denoted?

Back 98

different subscripts

Epi receptor in heart - alpha-subs
Epi receptor in vascular smooth muscle - alpha-subq

Front 99

what are two important examples of tyrosine kinases?

Back 99

insulin receptors

BCR-Abl receptor

Front 100

how do tyrosine kinase receptors function?

Back 100

after ligand-induced activation, these receptors dimerize and transphosphorylate tyrosine residues in the receptor and, often, on target cytosolic proteins

Front 101

what is the cause of chronic myelogenous leukemia?

Back 101

BCR-Abl, the tyrosine kinase, is always turned on

Front 102

how do steroid receptors function?

Back 102

small lipophilic molecules can diffuse through the plasma membrane and bind to intracellular transcription factors

ligand binding triggers a conformational change in the receptor and dissociation of a chaperone that leads to transport to nucleus

in nucleus, the ligand-receptor complex typically dimerizes and then binds to DNA, recruiting coactivators or corepressors

these complexes alter the rate of gene transcription, leading to a change (up or down) in cellular protein expression

Front 103

where can steroid hormone receptors be located?

Back 103

cytosol

nucleus

Front 104

what is a chaperone?

Back 104

repressor protein bound to a steroid hormone receptor that prohibits it from travelling to the nucleus until a conformational change is induced by the steroid hormone ligand

Front 105

what happens to a steroid hormone:receptor complex in the nucleus?

Back 105

typically dimerizes into a homodimer or a heterodimer

Front 106

what is an example of a steroid hormone:receptor heterodimer?

Back 106

thyroid hormone receptor with the retinoid X receptor