8/10/16 Clinical Applications of Pharmacokinetics - Pilch Flashcards
pharmacokinetics & drug admin
two patterns of drug admin
PK refers to the time-dependent changes in drug amounts (how blood level of a drug changes with time)
two patterns of drug admin
- continuous admin at constant rate (IV infusion)
- discontinuous admin - chronic repeated doses at reg intervals
continuous regimen / IV infusion
rate of entry vs. rate of loss
rate of entry
- constant
- zero order kinetics
- input = Ro (mL/min)
rate of loss
- depends on concentration (not constant)
- = total body clearance x plasma concentration
- first order kinetics
- output = kd x Vd x Cpl
on starting IV infusion, Cpl rises until it reaches steady state (Css), at which rate of entry = rate of loss
what is the relationship between Css and rate of entry?
how long does it take for steady state to be achieved?
- can you alter this by changing rate of infusion?
at steady state, rate in = rate out
Ro = kd x Vd x Css
the achievable steady state depends SOLELY on the rate of infusion!!!
- upping the rate of infusion DOES NOT change the time it takes to achieve steady state - it only affects the level of that steady state
general rule of thumb : it takes approx 4 half-lives to reach steady state concentration
- time taken is indep of Ro; linked to [1-e^(-kd * t)] portion of the eqn
- generally speaking, 1-2-3-4 halflives give you 50-75-87.5-94%
golden rules
- Css is directly proportional to infusion rate (Ro). Css is inversely proportional to total body clearance (CL = kd*Vd)
- rate of approach to steady state is indep of Ro; it depends solely on kd or t1/2 (t1/2 = .693/kd)
what do you do if 4 half-lives is too long to wait to reach target drug level???
IV bolus of dose you want (adjusted to prevent toxicity), followed by IV infusion at calculated rate
chronic dosing regimen
salient considerations
loading/maintenance regimen logic
important to consider:
- half life
- therapeutic index (toxic dose/effective dose ratio)
regimen is designed to keep you at a dose that achieves efficacy but doesn’t hit toxicity
- administer loading dose (2xED50), assuming this level does NOT hit toxicity (i.e. that the drug has a decent therapeutic index)
- administer maintenance dose (1xED50) every half-life to maintain efficacy
- t* = dosing interval
how do you calculate dosing rate and maintenance dose?
IV dosing rate
at steady state,
dosing rate = rate of elim = CLbody * Cpl_target
oral dosing rate has to be adjusted for bioavailability!
maintenance dose = (dosing rate / % bioavailability) * t*
modification of dosage regimens for renal disease
sensitivity?
clearance?
how should you determine if there’s going to be an issue with them? [what should you look at?]
- pts with renal disease have normal sensitivity to the drug
-
impaired clearance/elimination of the drug
- kd is smaller, so half-life increases
- how much depends on severity of disease and contribution of renal clearance to total body clearance
measure with : creatinine clearance!
- CLEARANCE OF DRUG WILL BE LINEARLY PROPORTIONAL TO CREATININE CLEARANCE
how should you modify dose for patients with renal disease?
ADJUST AT LEVEL OF CLEARANCE
look at CL_body as comprised of CL_renal + CL_metabolic
- adjust CL_renal for disease/impairment to get new kd_renalimpairment
- use it to calc an adjusted halflife
since renal impairment increases drug halflife, what should you keep in mind for fixeddose-fixedtime regimens?
how do you avoid it?
TOXICITY is now an issue!
- reduce dose by half
- double dosing interval
since renal impairment increases drug halflife…IV infusion implications?
how to avoid?
TOXICITY is an issue! (because Css is now double)
