Drug handling: Special patient groups
Older patients
Pharmacokinetic and pharmacodynamic changes in older patients may lead to altered drug response. All aspects of pharmacokinetics (absorption, distribution, metabolism and excretion) may be affected, although clinically significant effects due to changes in oral absorption are rare.
• Differences in body composition in older patients (e.g. reduced body water and increased body fat)
• Reduced serum albumin levels
• Alterations in organ perfusion, such as reduced liver and kidney blood flow due to decreased cardiac output and increased peripheral vascular resistance
• Reduced serum albumin levels
• Alterations in organ perfusion, such as reduced liver and kidney blood flow due to decreased cardiac output and increased peripheral vascular resistance
Decreased hepatic blood flow leads to a reduction in first-pass metabolism. Together with reduced microsomal oxidation, the capacity of the liver to handle drugs may be significantly impaired in older patients. This can lead to increased half-lives and higher steady-state levels of some hepatically metabolised drugs.
Renal excretion of drugs may be reduced in older patients due to a decrease in kidney size and loss of functioning glomeruli. Actual renal impairment on top of age-related reductions in function will obviously make drug clearance even worse. Note that older patients may have a normal plasma creatinine but still have a reduced creatinine clearance. Their decreased muscle mass produces less creatinine which can be balanced out by a decreased renal clearance, resulting in plasma levels within the normal range. Reduced renal excretion is particularly significant for drugs with a narrow therapeutic index (e.g. digoxin).
There are also pharmacodynamic changes with age such as an increased sensitivity to the sedating or hypotensive effects of medicines.
Altered pharmacokinetics in paediatric patients may have a significant effect on drug response.
There are probably no significant differences between adults and children in terms of oral absorption of medicines, but the distribution of drugs may be affected by changes in body composition. As a percentage of body weight, total body water and extracellular fluid volume decrease with age. This is important for water-soluble drugs such as gentamicin, where a larger dose on a milligram per kilogram basis is used in the neonate compared to an older child, to achieve the same plasma concentration.
Renal excretion of drugs may be reduced in older patients due to a decrease in kidney size and loss of functioning glomeruli. Actual renal impairment on top of age-related reductions in function will obviously make drug clearance even worse. Note that older patients may have a normal plasma creatinine but still have a reduced creatinine clearance. Their decreased muscle mass produces less creatinine which can be balanced out by a decreased renal clearance, resulting in plasma levels within the normal range. Reduced renal excretion is particularly significant for drugs with a narrow therapeutic index (e.g. digoxin).
There are also pharmacodynamic changes with age such as an increased sensitivity to the sedating or hypotensive effects of medicines.
Children
There are probably no significant differences between adults and children in terms of oral absorption of medicines, but the distribution of drugs may be affected by changes in body composition. As a percentage of body weight, total body water and extracellular fluid volume decrease with age. This is important for water-soluble drugs such as gentamicin, where a larger dose on a milligram per kilogram basis is used in the neonate compared to an older child, to achieve the same plasma concentration.
In premature babies, plasma protein binding is reduced resulting in higher concentrations of free (active) drug. This also leads to medicines having a higher apparent volume of distribution in premature babies compared to adults.
At birth, the capacity of the neonate to metabolise drugs is significantly lower compared to adults. However, there is a large rise in metabolic capacity in the older infant and young child. For some drugs, such as theophylline, the metabolic clearance in children may be greater than that seen in adults. This necessitates a larger dose on a milligram per kilogram basis in children to achieve plasma concentrations similar to adults. Metabolic pathways that make a minor contribution to adult metabolic capacity may be used more in children to compensate for their less developed systems.
Renal excretion of drugs in young infants is reduced due to anatomical and functional immaturity of the kidneys. However, towards 6-8 months of age, the glomerular and tubular function develops; by 8 months the renal elimination of drugs is approaching that seen in older children and adults.
For more information about the use of medicines in children, follow the link to the tutorial on this subject.
At birth, the capacity of the neonate to metabolise drugs is significantly lower compared to adults. However, there is a large rise in metabolic capacity in the older infant and young child. For some drugs, such as theophylline, the metabolic clearance in children may be greater than that seen in adults. This necessitates a larger dose on a milligram per kilogram basis in children to achieve plasma concentrations similar to adults. Metabolic pathways that make a minor contribution to adult metabolic capacity may be used more in children to compensate for their less developed systems.
Renal excretion of drugs in young infants is reduced due to anatomical and functional immaturity of the kidneys. However, towards 6-8 months of age, the glomerular and tubular function develops; by 8 months the renal elimination of drugs is approaching that seen in older children and adults.
For more information about the use of medicines in children, follow the link to the tutorial on this subject.
Extremes of bodyweight
Obesity or low bodyweight may have an impact upon the pharmacokinetics of some medicines.
For patients who are obese, drug distribution is the pharmacokinetic parameter affected the most. If lipophilic medicines are given at doses not adjusted for weight, there could be a risk of underdosing and therapeutic failure, as there is more fat mass for them to distribute into. For hydrophilic medicines which do not distribute into fat, care must be taken not to use a patient’s total bodyweight to calculate the dose as this could result in overdose and adverse effects (e.g. gentamicin, vancomycin, rifampicin).
Compared to dosing in obesity, information about drug handling in adults who have a low bodyweight is relatively lacking. However, some clinical trials may have included one or both groups and so the SmPC for a medicine may be a starting point (e.g. apixaban, paracetamol).
A related subject is the impact of bariatric surgery upon drug handling by the body. There are several different procedures but most result in the size of the stomach being reduced which can affect drug absorption and the choice of formulation. Other changes may include higher stomach pH and altered drug distribution due to the loss of fat mass. Refer to the Information sources page of this topic for more guidance.
Patients with impaired renal and/or liver function
The impact of impaired renal and/or liver function upon drug handling are covered in the renal and liver topics on this site.