Clinical Pharmacology and Therapeutics. Группа авторов
alt="An illustration of a magnifying glass placed inside a shaded circle."/> Clinical scenario
A 76‐year‐old man has been referred with sepsis probably secondary to a urinary tract infection. He is unwell and the hospital guidelines suggest giving him gentamicin. He has a past history of renal impairment which has been stable for some time. What information do you need to know and what dose of gentamicin would you give?
There a number of factors that contribute to a lack of therapeutic effect of a dosed drug in an individual
Blood monitoring of drug levels is a useful way of ensuring maximum benefit whilst minimising the risk of complications of a particular drug
Therapeutic drug monitoring is most useful for drugs such as digoxin, phenytoin and gentamicin which have a narrow therapeutic index
Introduction
There are various reasons why a prescribed dose of drug leads to a different plasma drug concentration and therefore clinical effect. These include:
Individual differences in absorption, first‐pass metabolism, volume of distribution and clearance
Altered pharmacokinetics because of gastrointestinal, hepatic or renal disease
Drug interactions
Poor adherence to therapy
For most drugs there is an accepted ‘target’ range, i.e. a range of concentrations below which the drug is usually ineffective and above which it is usually toxic. In order to maintain drug concentrations within this range, knowledge about factors that influence the relationships between drug dose and blood concentration is used to design dosage regimens. Dosage adjustments based on age, renal function, hepatic function or other drug therapies are often recommended, especially for drugs with a narrow therapeutic index. For example, the initial dose of gentamicin, a renally cleared antibiotic, is based on the patient's renal function. As a consequence of an interaction that increases digoxin concentrations, the dose of digoxin is usually halved when amiodarone is added to a patient's therapy.
Therapeutic drug monitoring
In many cases it is relatively easy to evaluate the pharmacological effects of a drug by clinical observation, and initial dosage regimens can be modified to increase the therapeutic effect or to eliminate unwanted effects. Measurement of drug concentrations in blood can be performed to help with diagnosis or to optimise therapy for those drugs where response (therapeutic or toxic effects) cannot be readily evaluated from clinical observation alone. Examples of drugs where monitoring can usefully aid clinical judgement, together with target ranges, are shown in Table 1.3.
As a result of pharmacokinetic and pharmacodynamic variability, the following factors should be considered when interpreting drug concentration measurements:
1 Is the patient responding to therapy or showing symptoms of toxicity?
2 Was the sample taken at steady state?
3 Was the sampling time appropriate for the drug?
4 Where is the concentration relative to the ‘target’ range (Table 1.3)?
5 If the patient is not responding or has toxicity, how should the dose be modified?
Unexpectedly low concentrations may indicate poor adherence or an absorption problem (e.g. secondary to vomiting).
Clearance estimates
The clinical significance of clearance is that it determines an individual patient's maintenance dose requirements. Clearance varies between individuals and within an individual in response to changes in his or her clinical condition.
The physiological and pathological factors that affect the clearance of a drug depend mainly on which organ is primarily responsible for its elimination. For example, clearance of the bronchodilator theophylline, a drug that is eliminated by hepatic metabolism, is influenced by age, weight, alcohol consumption, cigarette smoking, other drugs, congestive cardiac failure, hepatic cirrhosis, acute pulmonary oedema and severe chronic obstructive airways disease.
Table 1.3 Examples of target ranges.
| Drug | Target range | |
|---|---|---|
| Mass units | Molar units | |
| Digoxin | 0.8–2 μg/L | 1–2.6 nmol/L |
| Carbamazepine | 4–12 mg/L | 20–50 μmol/L |
| Phenytoin | 10–20 mg/L | 40–80 μmol/L |
| Gentamicin | 5–12 mg/L (1 hour post‐dose) | |
| Vancomycin | 5–10 mg/L (trough) | |
| Theophylline | 5–20 mg/L | 28–110 μmol/L |
In some hospitals, high aminoglycoside doses (e.g. gentamicin doses of 5–7 mg/kg) are given at intervals of 24–48 hours and the normal target peak and trough ranges do not apply. Samples are usually taken 6–14 hours after the dose and the dose is adjusted (if necessary) according to a nomogram.
Clearance in any individual is most accurately determined from concentration measurements. However, in many cases, relationships between clearance and clinical factors have previously been established. For example, the average value for theophylline clearance is 0.04 L/h/kg and this is modified according to the patient's clinical characteristics by multiplying by the factors shown in Table 1.4. This means that on average, smokers require 1.6 times the theophylline dose of non‐smokers and patients with cirrhosis require half the dose of patients without cirrhosis.
Table 1.4 Factors influencing theophylline clearance and therefore dose requirements.
| Factor | Adjustments required |
|---|---|
| Smoking | ×1.6 |
| Congestive cardiac failure | ×0.4 |
| Hepatic cirrhosis | ×0.5 |
| Acute pulmonary oedema | ×0.5 |
| Severe chronic obstructive airways disease | ×0.8 |
For drugs primarily excreted by the kidney, e.g. digoxin and gentamicin,