Therapeutic drug monitoring

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TOPIC 10 Therapeutic drug monitoring

Introduction 179

Gentamicin 180

Digoxin 180

Phenytoin 180

Theophylline/aminophylline 184

Vancomycin 184

Commonly prescribed drugs needing TDM 184

Introduction

Drugs that are suitable for therapeutic drug monitoring (TDM) have a recognized desired serum concentration range. Within this range the drug will produce its optimal effect with minimal toxicity. TDM is thus necessary for two reasons:

1. To determine the drug is at therapeutic plasma concentrations: for most drugs, the easiest way to determine efficacy is by achieving a clinical endpoint. However for certain drugs, TDM is the only way to ensure the drug is working.

2. To determine if the drug is at toxic levels: some drugs have a ‘narrow therapeutic range’, where the difference between efficacious and toxic concentrations is small. TDM aids drug dosing, keeping plasma levels within the desired efficacious range and out of the toxic range.

The drugs most likely to require TDM are gentamicin, vancomycin, phenytoin, digoxin and theophylline/aminophylline. When considering measuring a drug level, the following needs to be known.

Indication for TDM

• This may include achieving a therapeutic target, trying to avoid the toxic range, or both.

• Possible drug interaction. The drugs mentioned are prone to multiple drug interactions in relation to enzyme induction and inhibition.

• Change in renal or hepatic function. The drugs mentioned above are either renally excreted (gentamicin) or hepatically metabolized (phenytoin, digoxin, theophylline).

When to measure the drug level

Drug levels need to be taken at specific times to make sense of the results. It takes about 4–5 half-lives for a regularly administered drug to accumulate in the blood, at which point the drug is said to be in steady state. Ideally, one would wait for the drug to reach steady state before taking a level, but in the acute situation this luxury is not possible. Ideally before the drug has reached steady state, one should take one of the following:

• Trough level, i.e. sample immediately before the dose is due, when the drug concentration is at its lowest; or

• Peak level: timing depends on the half-life of a drug – the longer the distribution half-life, the longer the time before the drug concentration is at its highest.

Interpretation

The sample needs to be labelled with the time of sampling and the time of dosing. Without it, the result will be uninterpretable.

How to act on what you find

This is not always simple. When in doubt, get help! But before considering anything complex, ask yourself some simple questions:

• Was the patient compliant in the community?

• Is there a possible drug interaction?

If possible, find an alternative to the offending drug. If there is no alternative, but the offending drug is for a short course (e.g. an antibiotic), continue both drugs, monitor for signs of drug failure or toxicity and recheck levels when the offending drug is stopped. If there is no alternative, but the offending drug is needed for a more chronic duration, seek advice.

Gentamicin

There are two methods of gentamicin dosing, the ‘conventional’ method and the ‘once-daily’ method (Table 10.1). ‘Once-daily’ is extremely dangerous if used in patients with renal dysfunction, for this reason, some units only use ‘conventional’ dosing.

Table 10.1 Gentamicin dosing regimens

Conventional dosing

1–1.5 mg/kg IV with frequency depending on estimated creatinine clearance (CrCl). If CrCl:

• >70 mL/minute, 8-hourly

• 30–70 mL/minute, 12-hourly

• 10–30 mL/minute, 24-hourly

• 5–10 mL/minute, 48-hourly

Indication Avoid toxicity (trough) and efficacy (peak) How it is done Take a peak and trough level before the third dose or on day 2 Target The trough level should be <2 mg/mL. The peak should be 4–8 mg/mL Interpretation

If the trough level is >2 mg/mL, withhold the next doses until the level falls to <2 mg/mL

Adjust the dosage interval rather than the actual dose

If the peak is too low consult a pharmacist or microbiologist for advice

Once-daily dosing

If obese, do not use their actual weight, but calculate their corrected body weight

Contraindication Once-daily dosing is not appropriate for a CrCl <20 mL/minute, oliguria, haemofiltration, endocarditis, severe liver disease, cystic fibrosis, major burns, prophylaxis or infants <6 months Indication For safe and effective therapy How it is done Levels any time between 6 and 14 hours postdose Interpretation

Refer to the Hartford nomogram (Fig. 10.1)

If the levels are high, increase the interval between doses as per the Hartford nomogram

Fig. 10.1 Hartford nomogram for gentamicin once-daily dosing regimen.

For obese patients, use corrected body weight:

• Ideal body weight (IBW) in kilograms:

–IBW (male) = 50 kg in weight + (2.3 × every inch over 5 ft in height)

–IBW (female) = 45 kg in weight + (2.3 × every inch over 5 ft in height)

• Excess body weight (EBW):

• Corrected body weight (CBW):

Use if patient is >15% obese.

Digoxin

See Table 10.2 for the dosing regimen, and Box 10.1 for drugs that can increase or reduce levels of the drug.

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