PK Exam Flashcards
What is applied pharmacokinetics
the process of optimizing drug therapy in individual patients
What are the variables of drugs usually monitored serum concentration measurement
correlation btw serum concentration and efficacy and toxicity
low therapeutic index
variable pharmacokinetics and pharmacodynamics
What are the pharmacokinetics principles
variability (drug to drug, pt to pt)
prospective vs retrospective assessment
ADME
What are the pharmacodynamic principles: assumptions
dose response curve
receptor theory
free drug concentration at site of action vs total drug concentration in plasma/serum
What are the pharmacodynamic principles: variability
physiologic agonist/antagonist
genetic factors
severity of disease
distribution to site of action
protein binding
tolerance
active metabolites
What is the overall goal of serum concentration monitoring
utilize serum concentration as an aid in optimizing drug therapy in individual pts to max probability of desired effect and min toxicity
What is the key point of applied pharmacokinetics
the patients response is more important than the absolute serum concentration
What are the common misconceptions of therapeutic ranges
efficacy (always have even in range)
toxicity (always have even in range)
therapeutic range never changes (it can)
***ranges need to be individualized, everyone is different
What is bioavailability (F)
the percentage or fraction of the administered dose that reaches the systemic circulation of the patient
Bioavailability estimates only the extent of absorption; not the _____ of absorption
rate
What is chemical form (S)
drugs administered as a salt form of the active compound: must multiple by factor that represents percentage of active compound
What does the first pass effect describe
hepatic metabolism of drug before reaching the ststemic circulation
What is the first pass effect on bioavailability
end result on dose and administration
What is administration rate (RA)
average rate at which absorbed drug reaches the systemic circulation
What is volume of distribution (Vd)
the size of a compartment necessary to account for the total amount of drug in the body if it were present throughout the body at the same concentration found in plasma
What does low lipid solubility have to do with volume of distribution
smaller
What does high lipid solubility have to do with volume of distribution
larger
What does low protein binding have to do with volume of distribution (plasma)
larger
What does high protein binding have to do with volume of distribution (plasma)
smaller
What does low tissue binding have to do with volume of distribution
smaller
What does low tissue binding have to do with volume of distribution
larger
Factors that alter Vd and dosing: decreased tissue binding
mat occur in uremic patients with drugs like digoxin, decreases Vd, higher plasma concentrations, and decrease loading doses in uremic patient
Factors that alter Vd and dosing: decreased plasma protein binding
increase Vd which decreases plasma concentrations, fraction of free drug will increase, no adjustment needed
What is Vi
the initial compartment, rapid equilibrating compartment - blood and organs/tissues with high blood flow
What is Vt
tissue compartment, slowly equilibrating
The initial half life for drugs is the _____ half-life. The terminal half-life is the ______ half-life
alpha
beta
During a loading dose if the loading dose is calculated based on Vd, the initial observed plasma concentration may be higher than predicted, as Vi is smaller than ___
Vd
If the target organ during loading doses is in Vi what can occur
toxic events
Target organs appear to be in Vi: drugs of lidocaine, quinidine, procainamide what do you do when altering the loading dose
decrease the dose
-administer full dose at slow rate
-administer in repeated incremental bolus doses
Target organs appear to be in Vt: drugs of digoxin and lithium what do you do when altering the loading dose
no empiric dose adjustment
must wait for complete distribution to occur to make clinical assessment
Drug concentration
in the plasma (Cp) refers to a total amount of drug in the plasma, consisting of drug that is protein-bound and free
What does protein binding refer to
drug that is bound to plasma protein
What does free or unbound drug refer to
drug that is not bound by plasma protein, drug that is able to interact at the receptor site, and is therefore pharmacologically active (alpha or Fu)
How do we assess protein status
albumin
other proteins
-albumin
-prealbumin
-total protein
What are the factors that determine alpha in protein-binding sites not saturable
plasma-protein concentration
binding affinity
exception: (salicylates, valproic acid)
Low plasma protein concentration effect on bound drug, effect on Vd, effect on total drug concentration, effect on fraction of free drug,
net effect on free drug
effect on bound drug: decrease
effect on Vd: increase
effect on total drug concentration: decrease
effect on fraction of free drug: increase
net effect on free drug: no effect
What does normal levels of Cp total, Fu, and Cp free change to during low plasma protein when albumin decreases from 5 g/dL to 2.5 g/dL
Cp total: 10 mg/L to 5
Fu: 0.1 to 0.2
Cp free: 1 mg/L to 1
What are the components of elevated plasma protein concentration
acute phase reactive proteins
cirrhosis
alpha1-acid glycoproteins (AAG)
(follow patients clinical response)
What does uremia and phenytoin do to binding affinity
decrease binding affinity
net-effect (drug levels and patient response)
Monitoring free concentration are uncommon why
limited availability
increased cost
most patients have normal binding characteristics
little data to show better correlation with free than with total
As general rule is as alpha increases one should ________ Cp desired by the same proportion
decrease
Clearance
represents a theoretical volume of blood or plasma which is totally cleared of drug in a given period of time
In body size of a larger individual what is the effect of clearance adjusted on body weight, clearance adjusted on body surface area, effect on clearance, effect on drug concentration, effect on amount of drug removed at steady state, effect on patient response at steady state
effect of clearance adjusted on body weight: increase
clearance adjusted on body surface area: increase
effect on clearance: increase
effect on drug concentration: decrease
effect on amount of drug removed at steady state: equal
effect on patient response at steady state: decrease
During diminished protein binding (with a highly protein-bound drug what is the effect on clearance, effect on drug concentration, effect on amount of drug removed, effect on patient response
effect on clearance: increase
effect on drug concentration: decrease
effect on amount of drug removed: increase
effect on patient response: no change
What is extraction ratio
less than alpha
extr ratio > free drug ratio = less drug available for removal
proteins act as carrier to facilitate for removal
Drugs that effect renal function
digoxin
vancomycin
gentamycin
Drugs that effect hepatic function
lidocaine
Drugs that effect cardiac output
decrease in this causes a decrease in CL
blood flow dependent CL drugs
Is Cl(renal) and Cl(non-renal) independent of each other
yes
What Cl(non-reanl) a metabolite of
hepatic metabolism (but not always)
What is first order kinetics
a process in which drug amounts or concentration diminish logarithmically (amount of drug eliminated per unit of time changes, but fraction of eliminated drug stays the same)
What is elimination rate constant (Ke)
fraction or percentage of drug eliminated per unit of time
If Cl increase what happens to Ke
increases
If Vd increases what happens to Ke
decreases (half-life prolonged)
If Cl and Vd change proportionally then Ke does what
stays the same
If Cl and Vd change disproportionately then Ke does what
changes
Half-life (t1/2)
the time it takes for the total amount of drug in the body or the plasma concentration to decrease by 1/2
During steady state and time for drug elimination how many half-lives does it take to complete
4-5
What is first order decay represented by
e^-kt
At average steady state tao is significantly less than what
t1/2
(helpful for infusion model and intermittent dosing model)
What are the 2 assumptions in calculating C(ssmax)
Immediate and complete absorption and distribution
What is CrCL
the volume of plasma cleared of creatinine per unit of time
What age is elderly classified as
65 yo
Age range for young-old, middle-old, old-old
young-old: 54-74
middle-old: 75-84
old-old: 85 and older
What are age related factors that affect absorption (elderly)
gastric fluid pH and rate
GI blood flow and age related GI disease
nutrition
Effects of absorption (elderly)
dissolution
first pass effect (may be decreased which increase bioavailability)
Net effect and clinical significance on absorption (elderly)
rate
extent
non-oral dosage forms
Potential age related factors that may affect distribution (elderly)
body comp (decrease in water, increase in fat)
change in multi-compartment model
altered protein-binding
age-related disease
bed rest
Net effect and clinical significance on distribution (elderly)
protein-binding
hydro-lipo philicity
single vs multi compartment
Factors that may affect metabolism (elderly)
increase comorbidities, drug use, environment exposure
poor nutrition
decrease liver mass, hepatic blood flow
Effect of age on metabolism
deceased blood flow and liver mass
intrinsic metabolic function
Net effect and clinical significance of metabolism (elderly)
extraction ratio (high ER drugs will show decreased Cl due to decreased hepatic blood flow)
route of elimination
Potential age related factor that may affect excretion (elderly)
decreased renal blood flow, kidney mass, intrinsic function
Net effect and clinical significance of excretion (elderly)
renal clearance decrease
route of elimination
dose regimen
active metabolite
When is there an exception for start low and go slow for elderly
septic shock
What are the major reasons a patient will receive dialysis
acidosis
electrolyte imbalance
ingestion of overdose
overload
uremia
What are the two types of dialysis for CKD
intermittent hemodialysis (IHD)
peritoneal dialysis (PD)
What are the two types of dialysis for acute kidney injury patients
continuous renal replacement therapy
IHD
Common PK changes in AKI/Renal/CKD
decreased renal CL and metabolism
Increase Vd
altered protein binding to uremia
How to decrease dose in renal insufficiency
lower Cssmax, higher Cssmin, same Cssave
How to extend the interval for renal insufficiency
net result of same Css max/min/ave
mimic normal serum concentration
Do you have the change the loading dose in renal insufficiency
no except when there is fluid overload and first dose needs to be increased
What does dialysis do
removes toxins and waste products from the blood
IHD influences on Cl*
Molecular weight (<500 daltons)
Protein binding (too large to cross membrane)
Flow rate
Filter type (high vs low flux)
Components of dialysis drug removal*
Vd (unbound fraction)
Estimate patients CL
Dosing Interval (compare to 1/2 life)
Molecular Weight
What is standard hemodialysis
maintenance dose (between sessions)
Drug removed during dialysis then dose drug post-dialysis and calc replacement dose
True or False: IHD and CRRT have significantly different effects on drug clearance
True
What is the optimal bacterial killing peak/MIC
> 10
What is PAE (post-antibiotic effect)
continual suppression of bacterial growth after limied exposure
How is Vd effected in aminoglycosides
malnourishment
obesity
pregnancy
ascites
ill
Tissue compartments in aminoglycosides are generally lower than serum concentration except for what parts of the body
kidney
perilymph
inner ear
urine
How to estimate Vd based on weight (aminoglycosides)
use IBW
if actual BW < IBW use actual BW
morbidly obese use adjusted BW
If significant fluid retention has occurred in aminoglycosides how to estimate Vd
use actual BW and Vd (0.25-0.3 L/kg)
use IBW and Vd of 0.35 L/kg
What is essentially responsible for all drug removal in aminoglycosides
glomerular filtration
Normal elimination t1/2 in adults and children for aminoglycosides is how long
2-3 hours
What is the conventional method of dosing for gent/tobra
1-2mg/kg q8-12h
Principles for extended interval dosing for aminoglycosides
high peak/MIC ratio improve efficacy and resistance
PAE increases with increasing concentration
longer dosing interval allows for drug-free period
What are the limitations not accounted for on the monogram for aminoglycosides
no indication for infection
nothing about MIC
nothing about severity
no pharmaodynamics
no synergy
How to dose nomogram ER (hartfort) for CrCL 60 and above, 40-59, 30-39, less than 30
DOSE: 7mg/kg
INTERVAL:
>60: 24h
40-59: 36h
30-39: 48h
<30: traditional dosing method
Hartford nomogram limitations
one-compartment from traditional dosing methods
aminoglycosides at high doses differ significantly
similar kinetics are invalid
