Pharmacokinetics 3 Flashcards
what is Therapeutic drug monitoring (TDM)?
Therapeutic drug monitoring (TDM) is the practice of using drug levels, p/kinetics and p/dynamics to optimise drug therapy to individual patients
what is Therapeutic drug monitoring (TDM) typically used for?
1) Drugs with a narrow therapeutic index
2) Drugs where dose and effect are not strongly correlated
3) Drugs where Cp and effect are strongly correlated
4) Drugs with wide inter-patient variation in clearance
5) Drugs with toxicity that is not necessarily evidenced by easily observable symptoms
what is the equation for T.I?
T.I = TD50 ÷ ED50
- TD50 is toxic dose
- ED50 is effective dose
- the smaller the number of T.I the more toxic the drug is
Cp should be at steady state and the distribution phase should be complete before measurements are taken. what is the problem with using analytical methods to measure Cp?
Analytical methods will (most likely) return TOTAL Cp levels, with no distinction between bound and unbound drug.
- only the unbound drug can act
explain why Drug interaction with a strongly bound drug can become a problem
1) drug ‘A’ thatis 95% protein bound. A second drug ‘B’ is introduced which displaces bound drug from the protein, upping the free level by 3%
2) The free (active) drug level changes from 5% to 8%
3) This is a massive overall increase:8% / 5% = 1.6 times 4) increaseand so it is highly likely to cause a patient a problem
using valporic acid as a example, explain why Saturation of protein binding can become a problem
1) Valproic acid is ~90% bound to albumin at Cp of 75μg/ml
2) Above this Cp, the protein binding sites are saturated and an increased dose brings about a disproportionate rise in the free fraction of valproic acid
3) Therapeutic effect and clearance will rise in line with Cp(free)
the first step of therapeutic drug monitoring in a patient is information gathering. state what information is gathered
1) Patient’s physical details, clinical / biochemical status
2) Drug history, dosage regimes
3) Pharmacokinetic data (e.g. Vd and t1/2) for relevant drugs
4) Any prior pharmacokinetic information for the patient
5) Take blood and measure Cp
6) Work out what Cp ought to be using population values
7) Adjust KE until you get good agreement
after the information gathering stage. state the remaining steps involved in therapeutic drug monitoring
1) Use population pharmacokinetic data to calculate predicted Cp for when blood sample was taken
2) Compare to patient levels
3) Modify KE (remember CL = Vd KE) until predicted level matches actual
what should be checked If an individuals data does not match the data gathered from the population when they are being monitored?
1) concurrent drug therapy
2) compliance
3) medication error
4) mal-absorption
5) incorrect assay results
- complete distribution, equilibrium Cp ?
- laboratory error? e.g. incorrect sample storage
6) Patient kinetics may simply deviate from population kinetics
Creatinine is a breakdown product of creatine phosphate in muscles. what are the Useful properties of creatinine?
1) Creatinine is usually produced at a constant rate
2) It is not protein bound
3) It is filtered by the kidneys with little or no reabsorption
4) Accordingly, creatinine clearance is a good indication of patient renal function
5) Creatinine clearance approximates the actual glomerular filtration rate
the formula for creatinine clearance is Clcr= C urine × V urine ÷ C plasma. use the formula to work out the creatinine clearance from the following data:
- C urine is 1mg / mL
- V urine is in 1.33 mL / min
- C plasma is in 0.01 mg / mL
Clcr= 1.0 × 1.33 ÷ 0.01 = 133mL/min
- we work out creatinine function as it gives us an indication of the patients kidney function
24 hr urine collection not always convenient
, so we can estimate the creatinine clearance. how can we estimate the creatinine clearance of a patient?
1) Use Cockcroft-Gault formula
2) Cl cr est = (140-age) x weight x constant ÷ Cs (dont remember)
- Age is in years, weight is in kg. Cs (serum creatinine) is in μmol / litre. Estimated Clcr is returned in mL/min.
- Constant is 1.23 for men, 1.04 for women
which drugs do we therapeutically monitor?
1) Antiepileptics: e.g. Phenytoin, carbamazepine, gabpentin
2) Aminoglycoside antibiotics: e.g. Gentamycin
3) Cardiac: e.g. Digoxin, lidocaine
4) Theophylline, lithium, methotrexate, ciclosporin
