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Variability in drug dosage requirements

By Alison Thomson

The main challenge in designing a “standard” drug dosage regimen is the variability in drug handling that exists from patient to patient. Understanding the sources of this variability and adjusting drug doses accordingly is an area in which pharmacists can make a major impact on risk management and patient care.

There are three main sources of variability: those related to observable clinical characteristics, those that are genetically determined and those related to other drug therapy.

Age

Pharmacokinetic variability is particularly important at the extremes of age. This reflects differences in body composition and function. The weight-related volume of distribution of water-soluble drugs (eg, aminoglycoside antibiotics) is higher in neonates than in adults because of the greater proportion of water per kilogram of body weight. This means that if an adult and a neonate are each given a 5mg/kg dose of a water-soluble drug, such as gentamicin, the maximum concentration will be around 16–20mg/L in the adult and 10–11mg/L in the neonate. In contrast, the relative volume of distribution of fat-soluble drugs, such as diazepam, is higher in the elderly.

Age also affects drug binding. The binding of drugs to albumin in the plasma is reduced in neonates and in the elderly whereas binding to alpha-1-acid glycoprotein (an “acute phase reactant” that is released in response to inflammation and trauma) is generally low in infants but may be elevated in elderly patients, especially if other disease processes are present.

The clearance of drugs that are eliminated by the kidney is significantly influenced by age. Renal function is low at birth, particularly in premature neonates, and increases dramatically over the first two weeks of life, which means that the dose requirements of renally cleared drugs are highly variable during this period. In later years, renal function progressively declines and may be substantially reduced in elderly patients, despite apparently “normal” serum creatinine concentrations.

Age also affects the hepatic metabolism of drugs. At birth, most drug metabolising enzymes are present but the activity of many enzyme systems is low, so this can result in drug accumulation and toxicity. In contrast, the evidence that elderly patients have significantly reduced hepatic function is limited, and it is often unnecessary to reduce the dose of drugs that are cleared by hepatic metabolism unless other factors (eg, cardiac disease, hepatic disease or drug interactions) are involved.

Download the attached PDF to read the full article.

Citation: The Pharmaceutical Journal URI: 10997066

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