Pharmacokinetics Flashcards
what is pharmacokinetics
the study of the time course of drug concentration in the body, usually as reflected in the plasma concentration (fate of drug in the body).
first order kinetics is also referred to as what
exponential kinetics characterized by a constant fractional change per unit time
first order kinetics is measured as what
the rate constant (Ke)
zero order kinetics is also referred to as what
saturation kinetics
first order kinetics is characterized by what
a constant amount of change per unit time
half-time or biological half life (t 1/2)
for drugs that are eliminated by first-order kinetics, the fractional change in the amount of drug in the blood is generally expressed by the half-life. Time required for 50% of the drug remaining in the body to be eliminated (or the time required for the blood concentration to decrease 50%).
rate constant of elimination (Ke)
For drugs that are eliminated by first-order kinetics, the rate constant is the fractional change per unit time (fraction/min, fraction/hour, etc)
rate constant of elimination (Ke) is equal to what
0.693 / t1/2
OR
t1/2 = 0.693/ke
what is clearance
the quantification of elimination
for most drugs in clinical setting, clearance is
constant
clearance represents the volume of
biological fluid that would have to be completely freed of drug to account for the rate of elimination (ie. the volume of body fluid processed in a given time)
clearance is expressed as
volume per unit time
individual organ clearances are
additive
ie. take renal cl, pulmonary cl etc. and add the volumes up to give you total systemic clearance
clearance can be calculated from what
- excretion rate/concentration
2. dose/area under the curve (AUC)
compartmental model of pharmacokinetics
uses selected model to “fit” parameters to data
noncompartmental model of pharmacokinetics
most use the same basic principles (Trapezoidal rule; observed data; calculated elimination rate constant; standard formulas for the rest)
Fate of a drug
- liberation
- absorption
- distribution
- metabolism
- excretion
what is liberation
release from matrix
what is absorption
process and rate
what is distribution
movement in body
what is metabolism
removal by biotransformation
what is excretion
physical removal from body
what are key pharmacokinetic parameters
- clearance
- volume of distribution
- half-life
- bioavailability
what is volume of distribution
concept for a given dose, the theoretical size necessary to produce a specific calculated exposure
what is half-life
the length of time necessary to reduce or “eliminate” 50% of the current level of drug
what is bioavailability
the fraction of the dose that reaches systemic circulation
f=1 for IV
assumptions of a one compartment model
- the body is a single compartment with a volume (V) and drug concentration (C)
- distribution of drug is uniform and rapid compared with absorption and elimination
- elimination of the drug conforms to 1st order kinetics
see diagram: slide 10-11
see diagram: slide 10-11
assumptions of a two compartment model
- the body contains 2 compartments, central and peripheral
- all kinetics are first order
- elimination is form the central compartment
see diagram: slide 12 + 13
see diagram: slide 12 + 13
what are model independent parameters
- clearance, half-life, Vd
- AUC
- Cmax (max concentration)
- Tmax (time of max concentration)
see calculations: slide 16
see calculations: slide 16
what is the plateau principle
- when a drug is administered intravenously, the plasma concentration will increase until the rate of elimination and administration are equal
- at that point, the plasma drug [ ] will remain constant until there is a change in the dosage rate of elimination kinetics
steady state concentration (Css) equation
rate of administration/total body Cl = dosing rate/Cl
dosing rate equals
Cl x Css
Css equals
dosing rate/Cl
see diagram: slide 19
see diagram: slide 19
time required to achieve steady state depends on
half life
how many half lives does it take to achieve steady state
4-6 half-lives
see diagram: slide 21
see diagram: slide 21
conditions for fixed rate, multiple doses
- the drug will accumulate in the body if the time interval between doses is less than 4 half lives
- total body stores of the drug increase exponentially to a plateau
- the plasma [ ] will fluctuate during the dosing interval
- Css now represents the mean [ ] of the drug during the dosing interval
for oral dosing, what will also influence Css
bioavailability
what is bioavailability
is the fraction (f) of the administered dose that reaches the systemic circulation
what is the equation of Css in a fixed rate, multiple dose regimen
Css = (f) x dose / (dosing interval x Cl)
what happens to the [plasma] with a fixed rate multiple dose regimen
[plasma] will fluctuate btwn a maximum (peak) and a minimum (trough) concentration
see diagram: slide 24
see diagram: slide 24
for therapy characterized by repeated intermittent dosing, the choice of dosage interval is based on what
- tolerance btwn dose variations of serum concentraions (based on half life and toxicity of the drug)
- patient convenience plays a role for out patient therapy
when would a loading dose be administered
when the time to reach steady state is needed immediately
the amount of drug required to achieve a given steady-state value in plasma is the amount that
must be in the body when the desired steady-state is reached
what variable relates the total drug [ ] in the body to the plasma [ ]
Vd
loading dose equation is
loading dose = Css x Vd
what is nonlinear, dose-dependent or saturable elimination kinetics
a capacity-limited process where drugs exceed the metabolic/excretory capacity of the body to eliminate that drug as a linear rate
describe the clearance rate of a nonlinear elimination
Cl will vary with the [ ] of drug in a manner analogous to the M-M equation for enzyme kinetics
virtually all drugs taken by pregnant women are transferred to some degree across the
placenta to the fetus
delivery of single doses in pregnant women is limited by what
blood flow to the placenta
when does peak fetal blood concentration occur
btwn 20 mins and 4 hrs after IV dosing depending on the chemical characteristics of the drug
chronic dosing during pregnancy can lead to what
a steady-state
fetal:maternal [ ] approach unity
what are 5 critical time frames of pediatric pharmacology
- conception to birth
- birth to 1 month
- 1 month to 2 yrs
- 2 years to 12 yrs
- 12 yrs to 18 yrs
what drug characteristics affect developmental factors
- drug absorption
- drug distribution/% body water
- drug metabolism
- drug excretion
dosages are determined by
- formula
- body to surface area
drug disposition and aging is determined by what
- absorption
- distribution
- drug metabolism
how is absorption affect by age
relatively normal
how is distribution affect by age
aging is characterized by decreased lean body mass, increased % of body weight represented as fat, and decreased total body water
how is drug metabolism affected by age
-slower on average in the elderly due to decreased hepatic blood flow and smaller liver size
does the aging liver decreases its metabolism for all drugs
the aging liver to metabolize drugs does not decline in a similar way for all pharmacological agents, and the clearance of some drugs is largely unchanged (depends on intrinsic Cl)
what is the cockroft-gault equation
- estimates the glomerular filtration rate and generally
- obtained by estimating endogenous creatine clearance
what is cockroft-gault equation
CreatineCl = [140-age] [weight] / (72 x serumcr in mg/dL)
for women, creatinine clearance is –% of the value calculated by the Cockroft-Gault eqn
85%
why might the GRF be overestimated using the Cockroft-Gault eqn in older individuals with low [ ]
bc endogenous creatinine production from muscle is decreasing with age
how does age affect renal excretion
-aging is associated with decreased renal size and renal blood flow, leading to decreases in glomerular filtration rate
decreases in tubular function parallel those in
glomerular function
based on cross-sectional studies, creatinine clearance decreases an average of
8ml/min/decade after age 30
what dosage adjustments are done for renal dysfunction
- decrease dose, but maintain dosage interval
2. maintain dose, but increase length of dosage intervals
when is decreasing dose the preferred method of dosage adjustment for renal dysfunction
when a relatively constant plasma concentration of the drug is desired
