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RENAL > B. Why TDM? > Flashcards

B. Why TDM? Flashcards

1
Q

what is TDM

A

therapeutic dose monitoring: measurement of a chemical parameter that will directly influence drug dosing procedures

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2
Q

what strategy is used for a drug with a large therapeutic range

A

maximal dose strategy

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3
Q

what strategy is used for a drug with a narrow therapeutic range

A

target level strategy

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4
Q

what can be used to speed up the time to Css

A

a loading dose

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5
Q

loading dose equation

A

Vd x Css / F

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6
Q

what are dosing regimens designed to deliver

A
  • dose of drug
  • route of administration
  • interval between doses
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7
Q

what if plasma conc of drug enters the above upper limit conc

A

adverse effects (toxicity)

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8
Q

what if plasma conc of drug enters below lower limit conc

A

ineffective

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9
Q

what is the purpose of TDM

A
  • confirm safe and effective drug concentrations
  • investigate therapeutic failure (clinical trial)
  • check patient compliance
  • avoid or anticipate drug concs resulting in adverse effects
  • assess inter-patient variability

tailoring a dose regimen to an individual patient, by maintaining plasma concentrations within the therapeutic range

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10
Q

what factors affect TDM measurements

A
  • Pharmacodynamics (how drug affects body)
  • Pharmacokinetics (how body affects drug)
    Drug half-life
    Bioavailability
    Protein binding
    Clearance
  • Dosing regimen
  • Genetic polymorphisms
  • Sample type and timing
  • Testing methodology
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11
Q

how do genetic polymorphisms affect TDM measurements

A
  • genetic differences stable in different populations
  • different expression levels of different proteins
  • in CYP450 enzymes in liver which oxidise drugs in metabolism etc
  • example: CYP2C19 - 23% asian origin have a genetic polymorphism and only 4% caucasian origin so they will process drugs differently
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12
Q

what are the sources which cause PK variability

A
  • patient compliance
  • age
  • physiology: gender and pregnancy
  • disease: renal, hepatic, CV, respiratory
  • drug-drug interactions: CYP inhibition/induction
  • genetic influences: CYP polymorphisms
  • environmental influences: smoking, diet (grapefruit enzymes interact with CYP3A4)
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13
Q

what drugs have a narrow therapeutic index

A
  • lithium
  • phenytoin
  • digoxin
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14
Q

what drugs are highly protein-bound (so not bioavailable) or have interactions

A
  • warfarin (97% protein bound)
  • phenytoin (95%)

*if amount of albumin is decreased with renal disease, more drug will be cleared in urine

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15
Q

what patients have impaired clearance of a drug with a narrow therapeutic index

A
  • renal failure patients
  • digoxin (drug accumulation) as largely renal cleared
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16
Q

what drugs’ toxicity is difficult to distinguish from a patient’s underlying disease

A
  • theophylline and COPD as too high levels cause respiratory problems
17
Q

what drug’s efficacy is difficult to establish from their clinical condition

A
  • phenytoin (anti-epileptic)
18
Q

how are drugs typically given

A

oral or IV doses

19
Q

example of a repeated dose schedule

A

continuous IV infusion

20
Q

what does plasma drug conc increase to

A

steady state

21
Q

what is maxima called

A

peaks

22
Q

what is minima called

A

troughs

23
Q

infusion rate equation (R)

A

CL x Css

24
Q

oral dose equation

A

CL x Css x T (dosing interval) / F

25
Q

what kinetics occur with non-linear kinetics

A
  • saturating kinetics
  • enzymes saturated which metabolises drug (rate limiting step)

*alcohol consumption, no Css

26
Q

equation for rate of metabolism

A

Vm x Cp / Km + Cp

27
Q

what is Vm

A

maximum rate of elimination

28
Q

what is Km

A

Michaelis Menten constant: concentration at which we reach half the rate of metabolism

29
Q

when is linear PKs likely

A

therapeutic range < Km
*adsorption kinetics are rate limiting step

30
Q

when is non-linear (saturated) kinetics likely

A

therapeutic range > Km
*enzymatic turnover is rate limiting step

31
Q

what drug properties that require TDM

A
  • drugs with non-linear pharmacokinetics
  • narrow therapeutic ranges
  • above the upper limit the drug can have adverse effects (toxicity)
  • complex pharmacokinetics
32
Q

sources of variation in PK parameters between patients

A
  • normal genetic variation in expression of proteins involved in uptake, metabolism and
    secretion of drugs
  • variation in pharmacodynamics (natural way patients respond to drugs)
  • drug-drug interactions (+ food constituents) - competition for CYP450
  • age
33
Q

how is drug monitoring performed

A
  • by measuring plasma drug concentrations (used here)
  • by its clinical effect eg lowering of blood-pressure or the reduction in inflammation
  • by its biochemical effects eg glucose modulation by insulin or increase in
    prothrombin time by warfarin (indirectly)
34
Q

what is the most widely used sample

A
  • blood plasma or serum
    at steady-state
    convenient and standardised

*anticoagulant = plasma
*clotting factors = serum

35
Q

other types of samples

A
  • whole blood
  • CSF
  • saliva
  • urine
36
Q

analytical methodology for TDM

A
  • quantitative method with high throughput (results <24 hours)
  • distinguishes between compounds of similar structure – unchanged drug and metabolites (small changes make big changes)
  • detects low concentrations with high accuracy and precision (lots of components in blood)
  • simple enough to use as a routine assay
  • not affected by other drugs administered simultaneously (test sensitive to detect between drugs)
  • compromise between specificity and cost
37
Q

analytical methodologies used for TDM which involve drug polarity

A
  • HPLC (high performance liquid chromatography)
  • GC (gas chromatography)

*components of plasma separated
*non-polar stationary phase: solid (non-polar components move slower)
*polar mobile phase: liquid or analyte vaporised into inert gas (polar components move quicker)

38
Q

analytical methodologies used for TDM which involves antigen-antibody interactions

A
  • Enzyme-linked immunosorbant assay (ELISA): secondary AB enzyme-linked to produce a colourmetric/fluorescent marker we can quantify
  • Radioimmunoassay (RIA): most sensitive and expensive. Produce radioisotopes which we quantify with particular AB (radio labels)
  • Fluorescence polarization Immunoassay (FPIA): detect AB interaction by change in polarity of fluorescent molecule associated with AB when it binds an antigen for drug quantification

RENAL (13 decks)

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