Clinical Pharmacology and Therapeutics. Группа авторов
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 drugs are less bound to serum albumin and the decrease in binding correlates with the severity of renal impairment. The binding of basic drugs (to α1‐acid glycoprotein) undergoes little or no change
2 The structure of albumin is changed in renal failure and endogenous compounds may compete with drugs for binding
3 Haemodialysis does not return binding to normal, but renal transplantation does.
In most cases, changes in protein binding have limited clinical relevance and do not require alterations in dose. However, protein binding is important for the interpretation of serum phenytoin concentrations.
Influence hepatic disease on pharmacokinetics and pharmacodynamics
Hepatic metabolism
The hepatic metabolism of some drugs (e.g. nicardipine, propranolol) may be decreased in patients with renal failure. The reasons for this are not clear, but may indicate the presence of a metabolic inhibitor in uraemic plasma because regular haemodialysis appears to normalise the clearance of these compounds.
Altered drug effect
There are several examples of increased drug sensitivity in patients with renal failure. Opiates, barbiturates, phenothiazines and benzodiazepines all show greater effects on the nervous system in patients with renal failure than in those with normal renal function. The reasons are not known, but increased meningeal permeability is one possible explanation.
Various antihypertensive drugs have a greater postural effect in renal failure. Again the reasons are not clear, but changes in fluid balance and autonomic dysfunction may be partly responsible.
Worsening of the existing clinical condition
Drug therapy can result in deterioration of the clinical condition in the following ways:
1 By further impairing renal function. In patients with renal failure, it is clearly advisable to avoid drugs that are known to be nephrotoxic and for which alternatives are available. Examples include aminoglycosides, amphotericin, cisplatin, gold, mesalazine, non‐steroidal anti‐inflammatories, penicillamine and vancomycin
2 By causing fluid retention. Fluid balance is a major problem in the more severe forms of renal failure. Drugs that cause fluid retention should therefore be avoided, e.g. carbenoxolone and non‐steroidal anti‐inflammatory drugs (NSAIDs) such as indometacin (indomethacin)
3 By increasing the degree of uraemia. Tetracyclines, except doxycycline, have an anti‐anabolic effect and should be avoided
Enhancement of adverse drug effects
In addition to decreased elimination, digoxin is more likely to cause adverse effects in patients with severe renal failure if there are substantial electrolyte abnormalities, particularly hypercalcaemia and/or hypokalaemia.
Because potassium elimination is impaired in renal failure, diuretics that also conserve potassium (amiloride, spironolactone) are more likely to cause hyperkalaemia.
Influence of liver disease
Impaired liver function can influence the response to treatment