Patient Related Factors

PATIENT RELATED FACTORS

Age

Modification in protein-drug binding as influenced by age of the patient is mainly due to differences in the protein content in various age groups.

i. Neonates: Albumin content is low in newborn; as a result, the unbound concentration of drug that primarily binds to albumin, for example phenytoin and diazepam, is increased.

ii. Young infants: An interesting example of differences in protein-drug binding in infants is that of digoxin. Infants suffering from congestive cardiac failure are given a digitalizing dose 4 to 6 times the adult dose on body weight basis. This is contrary to one's belief that infants should be given low doses considering their poorly developed drug eliminating system. The reason attributed for use of a large digoxin dose is greater binding of the drug in infants (the other reason is abnormally large renal clearance of digoxin in infants).

iii. Elderly: In old age, the albumin content is lowered and free concentration of drugs that bind primarily to it is increased. Old age is also characterized by an increase in the levels of AAG and thus decreased free concentration is observed for drugs that bind to it. The situation is complex and difficult to generalize for drugs that bind to both HSA and AAG, e.g. lidocaine and propranolol.

Intersubject Variations

Intersubject variability in drug binding as studied with few drugs showed that the difference is small and no more than two fold. These differences have been attributed to genetic and environmental factors.

Disease States

Several pathologic conditions are associated with alteration in protein content. Since albumin is the major drug binding protein, hypoalbuminaemia can severely impair protein-drug binding. Hypoalbuminaemia is caused by several conditions like aging, CCF, trauma, burns, inflammatory states, renal and hepatic disorders, pregnancy, surgery, cancer, etc. Almost every serious chronic illness is characterized by decreased albumin content. Some of the diseases that modify protein-drug binding are depicted in Table 4.3. Hyperlipoproteinaemia, caused by hypothyroidism, obstructive liver disease, alcoholism, etc., affects binding of lipophilic drugs.

TABLE 4.3.

Influence of Disease States on Protein-Drug Binding

Putting in a nutshell, all factors, especially drug interactions and patient related factors that affect protein or tissue binding of drugs, influence:

1. Pharmacokinetics of drugs: A decrease in plasma protein—drug binding i.e. an increase in unbound drug concentration, favours tissue redistribution and/or clearance of drugs from the body (enhanced biotransformation and excretion).

2. Pharmacodynamics of drugs: An increase in concentration of free or unbound drug results in increased intensity of action (therapeutic/toxic).