Pharmacokinetics

Front 1

What is the goal of drug therapy?

Back 1

To attain a therapeutic effect without toxicity

Front 2

Why is it that "average" doses that achieve "average" blood conc. of drugs not adequate?

Back 2

Because every patient response differently and the GOAL of TREATMENT is NOT NECESSARILY to ACHIEVE THERAPEUTIC SERUM CONC.

Front 3

What are some examples of how drugs can be eliminated?

Back 3

Metabolism, Excretion, Dialysis

Front 4

Most drugs follow which type of kinetics?

Back 4

First Order (linear) kinetics which means the CONSTANT FRACTION and NOT AMOUNT of drug present in patient is REMOVED per unit time.

Front 5

What is a ZERO order type kinetics?

Back 5

This is a NON linear or SATURATABLE - a CONSTANT AMOUNT of drug is removed per unit time - it is INDEPENDENT of amount of drug present (ethanol, phenytoin, salicylates)

Front 6

Why are most drugs first order kinetics?

Back 6

B/C most enzymes of drug metabolism evolved to HANDLE A WIDE VARIETY of substances (not very specific) so they tend to have HIGH Km values (so low affinity) for any one substance. B/C most drug elimination is NOT NEAR the saturation at any given point the RATE of DRUG LOSS is LINEAR with the DRUG CONCENTRATION

Front 7

For a logarithmic plot (conc) vs time plot what will be the shape?

Back 7

It will be a decreasing straight line (neg. slope) this is the serum decay curve or the LOG LINEAR phase - only applicable for a FIRST ORDER KINETICS

Front 8

SLOPE of the decay curve on a log plot determines the what?

Back 8

the Ke or the elimination RATE constant - Ke has the units of inverse time. Ke = -slope x 2.303
to calculate half life from Ke (half-life=0.693/ke)

Front 9

What would happen to a first order drug that is induced or if it has a competitive inhibitor?

Back 9

If a drug is FIRST ORDER it will ALWAYS STAY first order

Front 10

Volume of distribution (Vd)

Back 10

It is a CONCEPTUAL volume and may NOT CORRESPOND to any ANATOMICAL value. It can be extrapolated as the Y axis intercept (at time 0) for the terminal linear phase

Front 11

Distribution phase

Back 11

drug distributing into tissues is the RAPID PHASE (drop) during an IV bolus administration - the slower phase represents the elimination

Front 12

Zero Order drug elimination is best characterized by what parameters?

Back 12

Km and Vmax NOT Vd and clearance

Front 13

Why are zero order drugs dangerous?

Back 13

Because any fractional clearance from the body decreases and any DECEPTIVELY APPARENT HALF LIFE INCREASES with INCREASING DOSE is from ELIMINATION PATHWAY OPERATING AT MAX CAPACITY there fore a SMALL DOSAGE increase MAY DRAMATICALLY INCREASE SERUM CONC. (NOT LINEAR)

Front 14

What happens when conc. in = conc. out?

Back 14

STEADY STATE drug concentration and can only be achieved with FIRST ORDER ELIMINATION

Front 15

Periodic dosing (vs constant infusion) will cause what shape?

Back 15

It will cause a WOBBLY steady state (practically it is steady state as long as it stays in the therapeutic window)

Front 16

Changing the dose of a drug either up or down will cause what to the steady state?

Back 16

It will cause the steady state conc. to rise or fall to a new steady state level

Front 17

Bioavailability (F)

Back 17

Fractional amt of a given dose of a drug that gets into the blood - (if it is IV then it is 100% or 1) if it is ORAL then F depends on the ABSORPTION AND the AMT METABOLIZED in the FIRST PASS THROUGH LIVER
F is a multiplier to determine what fraction of a dose actually makes it into the circulation

Front 18

Area Under the Curve or AUC

Back 18

is the integral of the DRUG CONC. vs time plot - depends on bioavailability (how much gets in) and how fast it is removed

Front 19

Volume of distribution (DEFINITION)

Back 19

describes the CONCENTRATION of drug in BLOOD depends on the DOSE that is ADMINISTERED
Conc=(Dose *F)/Vd

Vd is just a conceptual volume used to determine how the CONC. in blood relates to the DOSE administered

Front 20

How do disease states affect LOADING DOSES?

Back 20

Disease states can alter the Vd (i.e. more or less space in the body for the drug to distribute)

Front 21

Loading dose

Back 21

LOADING DOSE is ADMINISTERED to ACHIEVE THERAPUTIC CONC. RAPIDLY
Note that f IV drug infusion you have a TRANSIENTLY very HIGH LOCAL CONCENTRATIONS of drug may be achieved. don't try to administer dose TOO FAST - 3-5 min is good

Vd is used to CALCULATE the LOADING DOSE needed to reach an INITIAL TARGET BLOOD CONC.

Front 22

Clearance

Back 22

Clearance is a PARAMETER describes the FIRST ORDER ELIMINATION in the same way that Ke or ELIMINATION - HOWEVER Cl quantifies the CONCEPTUAL AMT of BLOOD CLEARED (versus the TIME in Ke)

Clearance does NOT always equal to the RATE of BLOOD FLOW into the eliminating ORGAN

THE CLEARANCE is important for determining the AMT of drug necessary to MAINTAIN the steady state

Front 23

What is the equation of STEADY STATE

Back 23

RATE in = RATE OUT
(F*dose)/Dosing interval=C(conc. @ steady state) *Cl

THIS gives the MAINTENANCE DOSE to be CONTINUED to maintain the DESIRED DRUG CONC.

Front 24

What can influence the STEADY STATE CONC of drug?

Back 24

Bioavailability, dosing regimen (dose and dosing interval) and the CLEARANCE can ALL influence the steady-state conc. of drug

Front 25

Disease states can cause changes in Steady state. HOW? and how compensate?

Back 25

Compensate changes in clearance by changing the DOSING. Compensate for dosing intervals changes the PEAKS and FLUCTUATIONS - MORE FREQUENTLY a drug is ADMINISTERED the LESS FLUCTATION

Front 26

Half-life (definition)

Back 26

Half-life is a hybrid parameter in terms of PHYSIOLOGY - FUNCTION of both CLEARANCE and VOLUME DISTRIBUTION

T1/2=(0.693*Vd)/Cl

A change in half-life may reflect a change in clearance rate or in volume of distribution or in BOTH

Front 27

What is the most important use of half-life?

Back 27

Predicting how long it takes for a PERIODIC DOSING REGIMEN to ACHIEVE a steady STATE CONC. in the BLOOD

Front 28

In general how many half lives does it take to achieve a steady state?

Back 28

4-5 half lives to achieve regardless of how often the drug is give or what the dosing or elimination parameter changes

Front 29

If a patient is TOXIC what do you do?

Back 29

YOU IMMEDIATELY try to REDUCE blood conc. STOP ADMIN the drug let the blood conc. DROP

Front 30

What parameter is important for determining the LOADING DOSE?

Back 30

Vd

Front 31

What parameter is important for determining the maintenance dose?

Back 31

Clearance

Front 32

What parameter is important for determining TIME to STEADY STATE

Back 32

Half life

Front 33

Change in half life implies what?

Back 33

A change in Vd or CL or both

Front 34

WHY is it dangerous to CHANGE THERAPY based on changes in HALF LIFE?

Back 34

b/c HALF LIFE is dependent on Vd and Cl --> if you have antagonistic effects on both you can HAVE NO CHANGE in HALF LIFE but will need to CHANGE the DOSING STRATEGY!

Front 35

Absorption is generally dependent on what factors?

Back 35

Blood flow, chemical nature of drug, formulation, disease-induced changes in perfusion or cell mucosa, INJURY to ABSORPTION SITE

Front 36

Which drugs readily cross lipid membranes?

Back 36

SMALL and UNCHARGED COMPOUNDS more readily cross lipid membranes than ionized species

Front 37

What is important for drugs in ambient pH changes

Back 37

Alterations in AMBIENT pH that favor unionized species will PROMOTE ABSORPTION

Front 38

Weak acids will be more permeant at what ambient pH?

Back 38

at LOW pH (i.e. in acidic environments) where the unionized HA predominates over the A-

Front 39

Weak bases are more permeant at what ambient pH?

Back 39

at HIGH pH (in a basic environment) b/c the uncharged state predominates

Front 40

FOR a weak base across a membrane which side (acidic or basic) is the weak base TRAPPED?

Back 40

The weak base is TRAPPED on the ACIDIC side b/c it is charged at that LOW pH (only the FREE BASE that is UNCHARGED PERMEATES

Front 41

What is the FIRST PASS EFFECT?

Back 41

Drugs absorbed in the GI tract enter the PORTAL SYSTEM and are delivered to the liver before ENTERING the systemic CIRCULATION - LIVER METABOLIZES a FRACTION of the DRUG BEFORE IT even REACHES BLOOD (systemic circulation)

Front 42

Three aspects of DRUG ABSORPTION that are important

Back 42

1. LAG TIME
2. EXTENT of absorption (bioavailability)
3. RATE of absorption

Front 43

Lag Time (definition)

Back 43

Time between administration of a dose and the absorption of the dose.

Can be altered by disease states or drugs

Dependent on PRODUCT formulation and GASTRIC EMPTYING times (most absorption typically occurs in SMALL INTESTINE)

Front 44

EXTENT of absorption (F)

Back 44

Influences the TOTAL AMOUNT of drug ENTERING the BODY - proportional to BLOOD CONC of drug at steady state.

Front 45

What are potential effects of decreasing bioavailability of a drug due to decreased extent of ABSORPTION from the DISEASE STATE?

Back 45

it could drop the DRUG BELOW the THERAPEUTIC LEVEL (lack of EFFECT) or it could cause it to have a SHORTER DURATION of EFFECT

Front 46

What are the potential EFFECTS of INCREASING the BIOAVAILABILITY?

Back 46

CAN move the drug dose to a TOXIC level or it could INCREASE the DURATION of the therapeutic effect

Front 47

Determinants of bioavailability

Back 47

a. product formulation
b. intestinal transit time
c. drug interactions
d. food intake
e. magnitude of FIRST PASS METABOLISM (blood flow to LIVER and the CAPACITY of liver to metabolize i.e. drug induction or inhibition)

Front 48

What happens when you decrease the LIVER's ABILITY to metabolize a drug?

Back 48

You will first of all INCREASE bioavailability (increasing F ) since you DECREASE the first pass effect and YOU ALSO DECREASE clearance b/c you can't clear the drug as well and therefore the RISE in SERUM CONC. is MUCH greater than EXPECTED according to only ONE of the PARAMETERS alone

Front 49

What are the advantages of a SLOW but efficient absorption?

Back 49

It can yield a drug that can be effective for a longer TIME or it can EVEN BOOST a SERUM CONC. TO A THERAPEUTIC LEVEL when normally it would not (caveat it can also make it TOXIC) also a SUSTAINED preparation can also DROP a drug to BELOW THERAPEUTIC levels

Front 50

Determinants of RATE of ABSORPTION

Back 50

a. PRODUCT formulation
b. DRUG INTERACTIONS
c. GI physiology/pathology

Front 51

What factors would you need to keep in mind if a drug is actively transported into tissues?

Back 51

DISTRIBUTION: ACTIVE transport into tissues (dependent on AFFINITY for transporter and activity and access to transporter)

Front 52

What factors would you need to keep in mind if a drug is very lipid soluble? Large? or IONIZED/unionized?

Back 52

DISTRIBUTION: lipid soluble means more SOLUBLE and FASTER distribution/ distribution in fatty tissue
Molecular size will affect where molecules can go. IONIZED and non ionized will affect TRAPPING

Front 53

What factors would you need to keep in mind if a drug is BOUND to proteins in the plasma?

Back 53

Distribution: ONLY FREE DRUG can diffuse or be transported FROM the BLOOD to TARGET - BINDING can ALTER RATE and EXTENT of distribution - sometimes BINDING is very STRONG EFFECT

Front 54

DISEASE states such as HYPOALBUMINEMIA or uremia or drug interactions can have what effect on BINDING proteins and DRUGS?

Back 54

DISPLACEMENT may POTENTIATE the effect of the DRUG i.e. LESS BP means MORE free drug is accessible - HOWEvER this is ONLY A TRANSIENT EFFECT because FREE DRUG is ALSO MORE READILY AVAILABLE for ELIMNATION and REDISTRIBUTION

Front 55

BULK uptake into sinks affects what parameter?

Back 55

Distribution

Front 56

Overall tissue perfusion has an effect on what parameter?

Back 56

Distribution

Front 57

What are some possible distribution pathways you need to keep in mind?

Back 57

from blood, to tissue sites of actions from TISSUE DEPOSITS/sinks

Front 58

Where is most drugs excreted?

Back 58

kidney

Front 59

Determinants of a drug's capacity to be FILTERED?

Back 59

a. SIZE
b. glomerular integrity (bound drugs can be filtered now + cl)
c. number of nephrons (decrease - cl)
d. Protein BINDING

Front 60

Kidney disease has what effect on elimination/filtration

Back 60

it depends Glomerular integrity being compromised will lead to INCREASED Cl (protein bound can now be cleared) and decrease in the # of NEPRHONS will DECREASE CL as well so depends on the drug

Front 61

How does active transport in the kidney tubules affect elimination?

Back 61

variety of acids and bases can COMPETE for reabsorption and can affect the elimination of a basic or acidic drug

Front 62

Digoxin elimination and which drugs will have an effect on DISTAL NEPHRON transport?

Back 62

Spironolactone, quinidine, and verapamil - co administration will increase SEREUM CARDIAC GLYCOSIDE conc (digoxin conc)

Front 63

Passive absorption of acids and bases occurs in what part of kidney?

Back 63

Collecting duct

Front 64

What will the effect of urinary pH on passive transport of drugs being eliminated?

Back 64

Weak acids (barbituates) are REABSORBED in acid urine b/c they are NON IONIZED in the acidic urine and therefore NOT TRAPPED. NOT all drugs are pH dependent depends on lipid solubility and pKA etc

Front 65

What will the effect of alkalizing your urine if you are abusing amphetamines (basic)?

Back 65

You will prolong the high b/c a BASIC urine will PROMOTE the REABSORPTION (and decreased elimination) of a weak base (amphetamines) and you will effectively decrease the elimination of the drug from your system

Front 66

URINARY flow rate has what effect on elimination

Back 66

increased flow will INCREASE EXCRETION of some drugs b/c it will decrease the TIME AVAILABLE for REABSORTION will DECREASE - only clinically important for patients with HIGH URINARY FLOW RATES

Front 67

Serum drug conc. should be the end point. TRUE or FALSE?

Back 67

FALSE. use it as a TOOL. use clinical judgement

Front 68

Serum concentrations can help sort out variablity among individuals in the relationship between CONC. in BLOOD and EFFECT?

Back 68

No it can't. It can only sort out variability in ABSORPTION, DISTRIBUTION, and ELIMINATION of drug not its actual effect on the ACTIVE SITE

Front 69

Confounding factors in interpreting serum conc. data

Back 69

a. sampling in distribution phase (somtimes its long) --> will be way too high - SOLUTION: SAMPLE just prior to next DOSE
b. Sampling before STEADY STATE - remember 4-5 halflifes
c. DRUGS that have active metabolites -- can compound
d. MEasured drug conc - has usually BOTH FREE and BOUND drug

Front 70

What are some uses of measuring drug conc?

Back 70

a. determine rate and EXTENT of drug absorption
b. USe of FREE drug conc measurement
c. determine variations in clearance between patients
d. INDIVIDUALIZE THERAPY see above

Front 71

When drug measurement conc. may NOT BE USEFUL

Back 71

a. NOT ACCURATE measurements
b. serum conc. CORRELATES POORLY with response of drug
c. DRUG has a WIDE therapeutic range or a measured clinical endpoint of response readily measured
d. Active metabolites are NOT MEASURED
e. USUAL THERAPUTIC RANGE is altered
f. pharmacokinetics are not valid
g. RECORDED time of measure is NOT ACCURATE