Final Flashcards
In pharmacodynamics, is the change in drug effect usually proportional to the change in drug dose or concentration?
No
-Drug concentrations often must reach certain threshold to exert pharmacologic effect, but provide diminishing returns at higher concentrations (toxicity)
Narrow therapeutic index drugs
Drugs in which small changes in dose may lead to therapeutic failure or toxicities.
Little separation between therapeutic and toxic doses
Subject to therapeutic drug monitoring based on PK/PD parameters.
Intersubject variability in narrow therapeutic index drugs
Low to moderate
Narrow therapeutic index drugs examples
Digoxin, warfarin, lithium, phenytoin, TAC/CSA, theophylline, most anti-infectives (aminoglycosides and Vanc)
Minimum inhibitory concentration (MIC)
Lowest antimicrobial concentration that prevents visible growth of a standard inoculum of organism after 24 hours of incubation under standard conditions.
Antibiotics with time dependent killing
Penicillins, cephalosporins, carbapenems, vanc, oxazolidinones, macrolides
Which Abx with time-dependent killing should you optimize time above MIC (time >MIC)
Penicillin
Cephalosporin
Carbapenem
Which Abx with time-dependent killing should you optimize AUC over MIC ratio?
Vanc
Oxazolidinones
Macrolides
Optimizing time over MIC (T>MIC)
Extending duration of infusion (continuous infusions) decreases peak concentrations, but extends time over MIC
In a continuous infusion T>MIC is about 100%
Area under the curve
Measure of the extent of exposure to a drug, taking into account clearance from the body.
Which antibiotics have concentration dependent killing?
Aminoglycosides
Lipopeptides
Lipoglycopeptides
FQs
Which antibiotics with concentration dependent killing should you optimize the peak/MIC ratio?
Aminoglycosides
Which antibiotics with concentration dependent killing should you optimize the AUC/MIC?
Lipoglycopeptides
Lipopeptides
FQs
PK parameters of vancomycin
Abs- IV- complete; oral-poor Vd- 0.7L/kg Metabolism: >90% unchanged Elimination: >90% urine Protein binding- 55% protein bound
Serum concentration monitoring for Vanc
Trough concentrations:
10-15mcg/mL for UTI, skin/soft tissue infections
15-20mcg/mL for other infections
AUC/MIC >400
Vanc dosing loading dose
20-35mg/kg as a single dose (max 3000mg)
Consider in critically ill patients, patients receiving renal replacement therapy
Rapidly achieves targeted vanc concentration but does NOT lead to faster time to steady state.
Doses are based on ACTUAL body weight.
Renal replacement and the PK of vancomycin
Renal failure- reduced elimination of vanc
Hemodialysis- generally give a loading dose and maintenance dose after dialysis.
CRRT- give vanc every 12-24 hours
Limitations of the Ryback Nomogram for Vanc dosing
Only for adults with weight 50kg-110kg
Only for CrCl 40-110mL/min
Not validated in unstable conditions
AUC monitoring of Vanc
AUC/MIC is a PK/PD parameter that predicts clinical cure rate for severe MSSA and MRSA infections.
AUC/MIC >400 is the best way to ensure positive clinical outcomes
AUC/MIC <600 reduces toxicities
Aminoglycosides PK parameters
Abs- complete IV/IM
Distribution- highly hydrophilic, minimal penetration to CSF and ocular tissues
Metabolism/elimination- Primary unchanged, Eliminated in urine
Protein binding <30%
Aminoglycosides conventional dosing
Only used for synergistic dosing with beta-lactam in endocarditis.
1mg/kg IV Q 8 hrs
Goal peak: 3-5mg/L
Goal trough: <1mg/L
Aminoglycosides extended dosing interval
Most patients with serious gram negative infections are treated this way Gentamicin/tobramycin: 5-7mg/kg IV Q24 H Peak: 15-30mg/dL Goal trough <0.5mg/L Drug free interval of 4-10 hours
Advantages of extended interval dosing
Optimization of PD parameters (Cmax/MIC)
QD dosing
Comparable cure rates
SImilar AE
Disease states affecting the PK/PD of aminoglycosides
Obesity
Renal dysfunction
Hemodialysis
Monitoring conventional dosing of aminoglycosides
Serum peak and trough concentrations at steady state (typically around 4-5 dose)
Peak: drawn 30-60 minutes after completion of aminoglycoside infusion (goal 3-5)
Trough- drawn 30 minutes prior to the next dose (goal <1)
Age and warfarin
Increasing age has been associated with an increase response to the effects of warfarin. People need lower doses of warfarin as they age.
Gender and warfarin
Men need higher warfarin doses than women
Weight and warfarin
Weight effects warfarin requirements in men.
Increasing BW= increasing warfarin dose