PK: therapeutic drug monitoring + DDIs Flashcards
use drug conc to do what 2 things?
individualise treatment
adjust dosing regimen
when monitoring drug, looking for what 3 things?
clinical outcome
- symptoms improving
- infection being treated
toxicity
- is px developing any ADRs = high dose :/
drug conc over time
Why is therapeutic drug monitoring necessary?
- identifies issues w dosing regimen: toxicity, efficacy
- individualise treatment
What dosing regimen issues can be identified by monitoring?
- wrong drug: within TW but still not working
- wrong dose: on lower end of TW or below MEC, but adherence is a consideration too
- whether toxicity is due to drug or disease progression
2 changes to consider if drug is wrong?
combination or diff drugs
What types of drugs typically need to be monitored?
- narrow therapeutic index
- variable PK profile (poor correlation between plasma concentration and dose)
- high risk patients: multimorbidities, polypharmacy/interactions affecting PK
What are examples of drug classes that need monitoring?
- antibiotics
- cardiovascular
- immunosuppressants
- cytotoxic drugs
- bronchodilators
- anti-epileptics
- lithium
- tricyclic antidepressants
Examples of antibiotics that require therapeutic drug monitoring
aminoglycosides (mycins), vancomycin
Examples of anti-epileptics that require therapeutic drug monitoring
phenytoin, carbamazepine, valproic acid
Example of cardiovascular drug that requires monitoring
digoxin
Examples of cytotoxics that require therapeutic drug monitoring
MTX
Examples of bronchodilators that require therapeutic drug monitoring
theophylline
What are examples of sampling considerations for monitoring?
- sampling logistics of blood
- timing
- free vs total concentration
- metabolite vs unchanged drug
How is sampling logistics a consideration for therapeutic drug monitoring?
sample collection, stability and storage of samples need to be considered
What do you consider with regards to timing and monitoring? What are the exceptions?
- want to ensure steady state reached before measuring (5x half life)
- exceptions: individualising treatment or aminoglycoside + vancomycin treatment
When considering timing and monitoring for efficacy, what must you do?
determine Css right before dosing to ensure drug level are stable
When considering timing and monitoring for toxicity, when do you sample?
sample when the highest concentration is expected
When considering timing and you have a drug with a long half-life or multiple compartment PK profile, when do you sample?
sample 6-8hrs after dosing
How many approximate half-lives does it take for steady state to be reached?
5
Under what circumstances is the free drug concentration measured?
(not routinely)
when drug protein and plasma binding is altered due to:
- medical conditions
- drug interactions (displacement - acidic drugs for albumin)
What are examples of medical conditions where drug binding is altered?
- renal/hepatic disease
- malnourishment
- cystic fibrosis
- cancer (less albumin present = more drug eliminated as more free drug)
What techniques can be used to separate free and bound drug? 3
- equilibrium dialysis
- ultrafiltration
- ultracentrifugation
Under what circumstances would you want to monitor the metabolite concentration?
- if pharmacologically active
- if it contributes to adverse effects and toxicity
What are examples of analytical techniques used to monitor for metabolites?
- immunoassays
- liquid chromatography
A patient is on the following dosing regimen: losartan, paroxetine and methotrexate for RA. Which drugs are they likely to be monitored for?
MTX
The same patient begins to experience nausea, vomiting and a low white cell count. What would your course of action be?
monitor MTX concentration to see if above maximum effective concentration
DDIs….
definition of a DD?
a drug affecting efficacy and or toxicity of another drug
DDIs categorised based on what 2 things?
mechanism
outcome
3 sections under mechanism to categorise DDIs?
pharmaceutical: int during manufacture, storage, incompatibilities
PK: int changes ADME
PD: activity/tox changed without PK
the outcome of a DDI can be
- beneficial
- deleterious
2 examples of DDI that are beneficial?
carbidopa + L-dopa
tazobactam + piperacillin
DDI may affect absorption rate/ extent.
what 5 things may be affected?
gastric emptying
dissolution rate/ pH change
GIT motility
complexation
change in first pass metab
drug that may increase gastric emptying?
metoclopramide
drugs that may change pH?
PPI or antacids
2 types of drugs that may affect GIT motility (transit time)?
opioids
anti-cholinergics
2 drugs that may affect complexation therefore absorption?
cholestagel
Ca supplements
DDIs may affect distribution through change in plasma/ tissue protein binding by doing what?
compete for same binding site - drugs w higher affinity/ binding constant displaces the other
often both drugs highly bound to proteins - change to therapeutic response and or tox
drug that gets displaced, does fraction existing as free or bound drug increase?
free.
this is the form that can distribute, be elim, have pharmacol activity
DDI may impact on metabolism and inhibit metabolising enzymes through what….
competitive inhibition
non-competitive
onset immediate
reversible
irreversible
difference between competitive and non c inhibition?
C: both drugs compete for same site
NC: both drugs bind at diff sites
onset - inhib of metabolising enzymes - is immediate as soon as what?
inhibitor conc high enough to be clinically relevant
difference between reversible and non reversible inhibition of metabolising enz?
R: immediate return to normal metabolism rates as soon as inhibitor removed
I: return to normal requires synthesis of new enz + px no longer exposed to inhibitor
DDI may impact on metabolism and INDUCE metabolising enzymes through what….
synthesis of new enz in liver
onset gradual
recovery gradual
synthesis of new enz in liver: affect of hepatic Cl, and Css?
increase
reduce
how long after induer stopped is baseline reached? recovered
2-3weeks
impact of metabolism effects depend on what?
how important metabolism is for drug
drug undergoing extensive FPM… change to BA
absorption AND excretion may be impacted through impact on what 2 possible types of transporters?
influx/ efflux
what specific transporter may be induced/ inhibited?
Pgp
dec intestinal abs
dec uptake in bran
inc tubular/bile excretion
(comp, induction, inhibition all possible)
if transporters located in kidney/ liver what PK increased?
elim
if transporters located in SI/ brain what PK increased?
absorption
2 types of excretion that may be impacted?
renal
bile
renal excretion may be channged in what 2 methods?
changes in urine pH
competition for active tubular secretion sites
acidic drugs exreted faster at higher/lower pH
higher
basic drugs excreted faster at higher/lower pH
lower
X causes inhibition of renal excretion
probenecid
aspirin inhibits excretion of what drug?
MTX
so adjust MTX dose if both given
TF: changing urine pH will change elim rate of ionisable drugs?
true
bile excretion involes hydrolysis of gut bacteria which ->?
enterohepatic recycling -> longer drug effect
5 things to consider w DDIs?
timeline: onset, duration
predictions
therapeutic index
sequencing: order of drug admin
dose: saturation of processes (high enough conc to become issue)
