Applied Pharmacokinetics Flashcards
Therapeutic window
Effective concentration but below (too) toxic concentration.
Steady state
Rate of drug in=rate of drug out
IV infusion: 4 half lives
Amt of drug infused dosn’t change time to reach steady state, onlythe concentration at which steady state is achieved.
Constant rate of infusion
IV drip
Takes four or more half-lives to achieve this steady state (~93%)
*For every drop in, one drop out
Drug accumulation graph
Is the drug elimination graph flipped over
Accumulation to steady state:
After 1 half life= 50% steady state
“” 2 half-lives=75% ss
3 hh=87.5% ss
4 hh=93% ss
Oral steady state
Still four half-lives
Concentration of drug at steady state is related both to the dose given and to its bioavailability.
Steady state of oral administration (graph wise)
Between low points (b4 next dose) and high pts (after previous dose was absorbed).
Peak concentration
The highest [blood] after dosing.
Trough concentration
lowest [blood] after dosing. Just before next dose
Fluctuation
variation between peak and trough.
After a single dose, [peak] is about 70% steady state.
Loading dose
Give twice as much drug to reach [target] moe quickly, then give regular doses
Maintenance dose
Regular doses after loading dose
Loading dose calculation
Dose=VdC0
Adjust for bioavailability (F):
Dose=(VdC0)/F
What determines [drug] at SS? (Css)
Equals dosing rate divided by amt and frequency and bioavailability
Concentration of drug at SS (Css)?
Css=[(DRF)/Cl] or DR=(CssCl)/F
Cl=proportional to half life
Dr: dosing rate
F=for IV drugs is 1.
Drug given to [blood]
Proportional: 2xdose=2x concentration
1/2 dose= 1/2 concentration
Slower the drug is eliminated, higher the concentration in blood
Inversely proportional.
Cl is 1/2= 2x [blood]
Faster drug is cleared, lower the [blood]
Clx2= 1/2[blood]
ppl issues for therapeutic window
Absorption @different rates
Different metabolisms, renal functions.
Sick, age, genetics, gender
Concurrent meds affect absorption, distribution, or elimination.
Differen sensitivities to effective and toxic concentrations.
Drugs hard to keep w/in therapeutic window are:
Drugs w/narrow windows
Drugs w/short half-lives
Drugs w/long intervals between doses.
Erratic drug formulations.
Drugs easy to keep inside therapeutic window:
Drugs with broad windows
Drugs with long half-lives
Short intervals between doses.
Guidelines for staying within the therapeutic window
- More often the dose, steadier balance between in and out.
- Shorter the half-life of a drug the greater the degree of fluctuation in blood concentrations.
- "”may have to give them more often to limit fluctuating
More frequent dosing, why not toxic?
Give a smaller dose more often to achieve same {blood}
Lengthen half life of short lived drugs by
Pegylation (attaches polyethylene glycol)
Timed-release
Depot preparations
Enterehepatic cycling
Dosing rate:
[(Target concentration ss)x Cl]/F
Therapeutic [drug] monitoring can tell us:
Are plasma concentrations of drug in therapeutic/toxic range?
Is the pt adequately eliminating the drug?
Is pt adhering to the dose regimen?
Why is therapy failing?
What does regimen needs to be given?
Data given: [concentrations] at two different point two half-lives apart, and info on current dosing schedule.
You can conclude?
Vd, F, Cl and t1/2
Synergy:
when one drug increases effect of another by pharmacodynamic action or by increasing [blood] of second drug.
Antagonism:
One druge decreases the effect of another
Pharmacodynamic Synergy of toxicity
Two drugs add to or have a synergistic action through a shared mechanism or pathway
SSRI’s and sumatriptan
Beta-agonist plus a vasodilator
Pharmacodynamic antagonism
Other drugs having opposing effects: fighting for same receptor
Indirectly: glucocorticoids and insulin.
Cisapride slows HR and conduction, adrenergic increases automaticity at other sites in heart tissue.
Pharmacokinetic synergy of toxicity through metabolism:
Inducer of P450 increases activation rate of a prodrug.
Or increase creation of toxic metabolites
An inhibitor of P450 decreases elimination of drug***most common toxicity reason.
Pharmacokinetic synergy of action: renal and absorption
One drug can either decrease or increase renal elimination of a second drug. Thiazide diuretics increase lithium Other increase reabsorption. Probenecid inhibits aspirin secretion. Cholinergic speed gastric emptyingtime.
Pharmacokinetic synergy of toxicity through distribution
One drug displacing a second from plasma proein binding, inreasing [free/active] of the drug.
Occasionally, one drug will increase the distribution of another.
Manitol opens BBB
Pharmacokinetic antagonism through elimination or decreased activation:
One drug can speed up elimination of another:
1. Inductions: phenobarbital and birth control
2. 2a to diuresis: help wash out many drugs
3. Ion trapping: carbonic anhydrase inhibitors and barbiturates.
One drug can slow down activation of a prodrug: Cimetidin and sulndac
Pharmacokinetic antagonism through decreased or delayed absorption:
A few bind to many others in GI and prevent absorption.
Sucralfate and cholestyramine (inhibits digoxin absortpion)
Calcium carbonate and several drugs.
Others slow down GI or speed up GI altering absorption.
Drugs most commonly involved in Toxic Interactions
Narrow therapeutic window.
Drugs that boost them to toxic level or lowerthem to subtherapeutic levels.
Others add to pharmacodynamic effect.
Toxicity triggered by bullydrugs.
Worst bully drugs: inhibitin P450
Ketoconazole Cimetidin Ritonavir Cyclosporine Spironolactone
Worst bully’s that activate P450
Rifampin
Phenytoin
Phenobarbital
Carbamazepine
Block renal secretion/reuptake
Probenecid
Aspirin
Cause increased renal elimination
Diuretics w/renally eliminated drugs.
Victim drugs; become toxic easily
Theophylline LIthium Digoxin warfarin Coumarin Tolbutamide MAOI
Victims due to reduced action
Low bioavailability: digoxin
Easily eliminated byP450 inducers: birth control
Most common drug interactions occur with: (victim drugs)
Theophylline Lithium Digoxin Warfarin Coumrin Tolbutamide MAOI
4 mechanisms by which victim drugs become toxic:
- Pharmacodynamic interactions: Add adrenergic to Theophylline or MAOI; add second blood thinner to warfarin.
- P450 inhibition: ketoconazole increases warfarin, tolbutamide, theophyllne.
- INteract with diuretics: LIthium increased, digoxin increased by hypo-kalemic inducing diuretics.
- INteracting with protein binding: warfarin, tolbutimide, coumarin are highly bound but:
Sulfonamides, aspirin and others can displace them.
Ketoconazole Increases:
Warfarin
Tolbutamide
Theophylline
Diuretics increase
LIthium and digoxin
Adrenergics interact with:
MAOI and Theo
Sulfonamides and aspirin displace what from proteins
Warfarin
Tolbutamide
Coumarin
Birth control easily eliminated by
P450 inducers
