Exam 3 Flashcards
what is D?
dose
what is tau?
dosing interval
what is D/tau
dosing rate
at how many half lives does tau have to equal so that each dose behaves like a single IV bolus, complete elimination before new dose, no accumulation of the drug?
5 half lives or greater
typical clinical situation, drug accumulates in plasma (accumulation factor), Cmax and Cmin increase with each dose up to a point, steady state reached after certain time but time to reach SS depends on k (therefore half life), no further accumulation after SS (Cmax and Cmin remain constant after SS)
tau is less than 5 half lives
stable condition that does not change over time or in which change in one direction is continually balanced by change in another, accumulation does not change with each dose, Cmax and Cmin remain constant, concentration fluctuates between Cssmax and Cssmin where the goal is to keep Cssmax and Cssmin in therapeutic range
steady state
time to SS does NOT depend on……
dose (D) or dosing interval (tau)
balance between drug entering and leaving plasma, dosing rate is constant, elimination rate increases as plasma concentration increases (proportional), elimination rate eventually equals dosing rate
why SS is achieved with multiple dosing
what don’t we know at steady state?
peak and trough concentrations, whether or not within therapeutic range
compares Cmax after n doses to max concentration after first dose, depends on n, k, and tau but does NOT depend on dose, if this equals 1.0 there is NO accumulation but this also cannot be less than 1.0!
accumulation factor, Raccum
if tau increases, what happens to Raccum and why?
Raccum decreases because more time between doses means more elimination
if half life increases (k decreases), what happens to Raccum and why?
Raccum increases because it takes longer for the drug to be reduced by half so it accumulates more
at steady state, the concentration does this between Cssmax and Cssmin, depends on tau and k, does NOT depend on dose
fluctuation
what factors affect Css?
clearance, Vd, dose, dosing interval
if you increase dose but leave tau constant, what happens to Css and difference between Cssmax and min? what about fluctuation?
increases, no change in fluctuation
if tau is less than half life, what happens to fluctuation and accumulation?
fluctuation is smaller, accumulation is higher
if tau is greater than half life, what happens to fluctuation and accumulation?
fluctuation is greater, accumulation is lower
if we dose more frequently (decrease tau), need smaller or larger dose to avoid toxicity while retaining efficacy?
smaller
if we dose less frequently (increase tau), need smaller or larger dose to achieve efficacy without toxicity?
larger
for drugs with long half life, does it take longer or shorter to reach SS?
longer
high first dose to immediately reach desired SS concentration
loading dose, DL
start regimen at regular dosing intervals to maintain Css
maintenance dose, Dm
series of short IV infusions, infusion stopped before reaching SS, infusions given over regular dosing intervals (tau), compromise between multiple IV bolus and constant IV infusion (avoids high peaks of multiple IV bolus with less risk of drug related adverse effects)
intermittent IV infusion
time after first infusion is begun
t’
post infusion time equals…..?
tau - t’
how do we reduce fluctuation in intermittent IV infusion?
make post-infusion time smaller (for example increase t’ and keep tau constant)
time after last infusion was STOPPED
t*
when is fluctuation less acceptable?
when drugs have a narrow therapeutic index
nonlinearity can be due to the effect of….?
saturation of enzymes, disease (change in physiology), drug interactions
elimination kinetics are not first order, elimination half life and k change with dose of drug (half life increases as dose increases), plasma concentration increases disproportionately with dose, AUC is not proportional to amount of bioavailable drug
nonlinear kinetics
maximum rate of reaction in nonlinear kinetics
Vmax
drug concentration at which reaction occurs at half Vmax, inversely related to enzyme affinity for drug (increased this means decreased enzyme affinity for drug)
Km
as Vmax increases what happens to elimination rate?
increases (drug stays in body for less time)
as Km increases what happens to elimination rate?
decreases (drug stays in body for more time)
as Vmax increases what happens to AUC?
decreases (if elimination is faster less of the drug is bioavailable)
dosing rate
R
the initial rate of drug biotransformation increases, saturation occurs at lower Cp (toxicity at lower doses), patients with this exhibit greater changes in rate of elimination when dose is changed leading to greater adverse effects
decreased Km
enzyme induction and liver disease can affect Vmax or Km?
Vmax
competitive inhibitors can affect Vmax or Km?
Km
as dose increases in nonlinear kinetics what happens to half life, clearance, and AUC?
increases, decreases, increases
drug increases the expression of the enzymes responsible for its elimination, promotes its own destruction
auto-induction
drug/metabolites inhibits the metabolism of parent drug
auto-inhibition
occurs primarily via the circulatory system, mixing of drug in blood is very rapid, only a small amount of drug reaches site of action, relative distribution of drug between plasma and rest of body
drug distribution pattern
amount of plasma in an average person
3L
amount of extracellular fluid in an average person
15L
amount of total body water in an average person
40L
what is the ultimate barrier that drugs have to get through?
cell membranes
do lipophilic or ionized drugs have an easier time crossing cell membranes?
lipophilic
blood flow variable (blood flow to the tissue)
Q
tissue volume variable (how large tissue is)
V
lipid solubility, related by this variable, organ drug concentration over venous drug concentration ratio, greater this means greater ability to go to tissues
R
first order distribution rate constant
kd
the greater the distribution half life, the longer or shorter it takes for drug to enter and leave tissue?
longer
what tissue has the longest distribution half life because it has very low blood supply?
fat
for most drugs the rate of delivery from the circulation to a tissue depends on what?
blood flow, Q
do highly or lowly perfused organs/tissues rapidly attain drug concentrations?
highly perfused
higher logP means greater or smaller lipophilicity?
greater
high Po/w means high or low lipid solubility that penetrates most membranes?
high
low Po/w means high or low lipid solubility, does not penetrate BBB for decreased risk of CNS toxicity
low
high Po/w means high or low R?
high
in liver, heart, renal failure there is an (increased/decreased) cardiac rate and perfusion to tissues, (increased/decreased) rate of drug distribution, (increased/decreased) drug levels in tissues
decreased for all
