is much lower than expected and suggests poor adherence with therapy.
Why was the second concentration so high?
The predicted concentration on her increased dose can be calculated as before, i.e.
In this case, the measured concentration was reasonably consistent with the predicted value and her actual Vmax can therefore be estimated from the measured concentration, i.e.
Using her actual Vmax and a Km of 4.4 mg/L, average steady‐state concentrations can be predicted for various doses (Table 1.6). Note that a small change in the dose produces a disproportionately large increase in concentration, especially at higher concentrations.
Table 1.6 Predicted steady‐state phenytoin concentrations for clinical scenario.
| Dose (mg/day) | Steady‐state concentration | |
|---|---|---|
| (mg/L) | (μmol/L) | |
| 225 | 6 | 24 |
| 250 | 7 | 28 |
| 275 | 9 | 36 |
| 300 | 13 | 52 |
| 325 | 18 | 72 |
| 350 | 28 | 112 |
| 375 | 55 | 220 |
It is known that a concentration of 6 mg/L does not control her seizures and she experiences toxicity with 28 mg/L. Her ideal dose is therefore likely to lie in the range 275–325 mg/day. It would be sensible to start with 300 mg/day and adjust the dose (if necessary) according to her response. It would also be useful to emphasise to the patient that she must comply with her prescribed dose in order to obtain the maximum benefit from her therapy.
Comment. This case illustrates the non‐linearity of phenytoin dose–concentration relationships and the difficulty of interpreting phenytoin concentrations when dosage history is uncertain (as frequently occurs with outpatients). It also demonstrates the value of using serial measurements (the two results were clearly inconsistent with each other) and average dose requirements to assess adherence.
Influence of renal function on pharmacokinetics and pharmacodynamics
Drugs are usually considered in terms of their effect on disease processes. However, several diseases can influence the pharmacokinetics of a drug or its pharmacological effect on target organs. Diseases of the liver and kidney are of particular importance due to the role of these organs in elimination of drugs. This chapter will discuss the important considerations which arise when prescribing for a patient with these co‐morbidities.
A 45‐year‐old woman is admitted to hospital with severe urosepsis. She gives a background history of recurrent urinary infections and chronic renal impairment secondary to structural abnormalities of the urinary tract. Blood and urine culture reveals growth of Gram‐negative bacilli sensitive to gentamicin. How may this patient's renal function influence the treatment of her presenting complaint, and what precautions should be considered?
Influence of impaired renal function
Impaired renal function can influence drug therapy for the following reasons:
1 Pharmacokinetics may be altered as result of:Decreased elimination of drugs that are normally excreted entirely or mainly by the kidneysDecreased protein bindingDecreased hepatic metabolism
2 Drug effect may be the altered
3 Existing clinical condition may be worsened
4 Adverse effects may be enhanced
Altered pharmacokinetics
Elimination
Because the kidney represents one of the major routes of drug elimination, a decline in renal function can influence the clearance of many drugs. If a drug normally cleared by the kidney is given to someone with decreased renal function without altering the dose, the steady‐state blood concentrations of that drug will be increased. This is of considerable importance in the case of drugs showing concentration‐related effects, particularly those that have a narrow therapeutic range.
When such drugs are given to patients with renal dysfunction, the general aim is to achieve similar concentrations to those seen in patients with normal kidneys.
Therapeutic concentrations can be maintained by:
1 Determining renal function, usually by estimating creatinine clearance
2 Modifying the dose using a nomogram, either by increasing the dosage interval, or by giving a lower dose at the same interval or by altering both the dose and the interval. The extent and precision of dose modification depend very much on the toxicity of the drug concerned. In the case of the aminoglycosides, even minor impairment of renal function requires some dosage alteration, while the dose of penicillins need only be reduced in severe renal failure (creatinine clearance <10 mL/min). Guidance on dosage modification is readily available for most commonly used drugs. It should be noted that the loading dose is usually not changed by renal impairment because this depends more on the volume of distribution of the drug than its rate of elimination
3 Monitoring drug concentrations. This is useful for drugs with concentration‐related adverse effects, such as the aminoglycosides, digoxin, aminophylline, phenytoin and carbamazepine, and mandatory for lithium, ciclosporin (cyclosporin) and methotrexate. Nomograms are useful guides to the doses likely to be appropriate, but every patient is different. Concentrations of drugs in the blood can be used to assess clearance and to determine the most appropriate dose for individual patients
Decreased protein binding
The following changes occur in patients with impaired renal function:
1 Acidic
