Pharmacokinetic and Pharmacodynamic Factors That Can Affect Sensitivity to Neurotoxic Sequelae in Elderly Individuals

Gary Ginsberg; Dale Hattis; Abel Russ; Babasaheb Sonawane

Disclosures

Environ Health Perspect. 2005;113(9):1243-1249. 

In This Article

Liver and Kidney Disease in Elderly Individuals

The preceding discussion focused on subjects with no overt liver or kidney disease and so could be described as the natural course of aging of hepatic and renal function. However, disease-induced decrements in liver and kidney clearance of xenobiotics are an important overriding factor leading to altered pharmacokinetics and possibly increased variability in elderly individuals.

Although some organ diseases occur at other ages as well, their prevalence and severity are generally greater in elderly individuals because of more time for accumulation of damage and decreasing functional reserve (Mahon and James 1994). The senescent liver has reduced regenerative capacity such that recovery is impaired in response to viral or toxic insult or disease process (Regev and Schiff 2001). Diseases such as alcohol-induced cirrhosis, viral hepatitis-induced cirrhosis, hepatocellular carcinoma, diabetic-associated chronic liver disease, and biliary cirrhosis are more prevalent in the elderly and are associated with replacement of functional tissue with fibrotic or tumorous tissue or fatty lesions (Adler et al. 2002; Amarapurkar and Das 2002; Jansen 2002; Van Dam and Zeldis 1990). These changes can affect hepatic blood flow and the mass of metabolizing tissue available for drug clearance.

A variety of drugs can induce hepatotoxicity with the possibility that reduced cellular defenses and reserve capacity could make the elderly individuals' liver more susceptible to these drugs. For example, serum transaminases were used as an index of hepatotoxicity from combined isoniazid/rifampin therapy in pulmonary tuberculosis patients (Van Den Brande et al. 1995). Before antituberculosis treatment, serum transaminase levels were similar in a group of 67 young patients (mean age, 38.6 years) and 64 elderly patients (mean age, 71.2 years); subjects with pre-existing hepatic disease were eliminated from the study. During the course of treatment, serum transaminase levels in the young group increased approximately 2-fold, whereas a statistically greater increase of 4- to 5-fold was seen in the elderly group. Another study found that the incidence and severity of hepatic side effects of antituberculosis therapy were high in the elderly individuals, especially those with pre-existing hepatitis (Schaberg et al. 1996).

Sensitivity to drug-induced hepatotoxicity is likely dependent on a number of factors, including capability of hepatocytes to activate and detoxify the particular drug or chemical. Thus, one cannot generalize that elderly individuals will always be more sensitive to the effects of hepatotoxicants. However, where drug-induced hepatotoxicity does occur in elderly individuals, as exemplified by the antituberculosis drugs, one can expect there to be reduced hepatic extraction of other xenobiotics leading to the potential for toxic drug interactions.

Another chemical-induced hepatic effect that may be more prevalent in elderly individuals is liver cancer. This may be counterintuitive from the perspective that carcinogen exposure at a late stage in life leaves little time for expression of the chemical-induced genetic or biochemical change. However, a number of studies have shown a greater increase in liver tumors in response to promotional carcinogens (phenobarbital, peroxisome proliferators) when dosing was initiated in aged as opposed to young adult rats (Cattley et al. 1991; Kraupp-Grasl et al. 1991; Ward et al. 1988). The mechanism for this age-related vulnerability may be that promotors act on clones of cells that already have been transformed by an initiating (typically genotoxic) carcinogen. The number of initiated clones is believed to increase throughout the life span as a result of cumulative exposure to initiators, thus giving promotors a larger population of cells to act on in elderly individuals (Cattley et al. 1991).

Renal disease is also more common in elderly individuals. The chronic effects of hypertension and type 2 diabetes on the renal vasculature lead to renal diseases involving nephroschlerosis, atherosclerosis, and atheroembolism (Gomez et al. 1998; Mulder and Hillen 2001; Ritz and Tarng 2001). Nephropathy and reduced renal blood flow can progress to end-stage renal disease and the need for dialysis. Even before this point, renal disease can lead to decreases in renal blood flow, glomerular filtration, and tubular transport processes (Lam et al. 1997). This can be expected to decrease the clearance of water-soluble drugs and drug metabolites that rely upon glomerular filtration or tubular secretion mechanisms for entry into urine. Plasma protein binding can also be further diminished as greater amounts of these proteins are lost from blood into urine. Given that the effects of renal disease on the clearance of drugs are combined with the normal aging decrement in renal function, titration of drug dosage to renal function as estimated by creatinine clearance is especially important in elderly patients (Lam et al. 1997).

A variety of drugs can produce renal side effects, such as nonsteroidal anti-inflammatory agents, aminoglycoside antibiotics, amphotericin B, and acyclovir. The elderly are generally more sensitive to the renal toxicity caused by these agents because their elimination is already compromised because of aging-related decreased renal function, leading to greater concentrations in blood and kidney (Johnson et al. 1994; Muhlberg and Platt 1999). This drug-induced worsening of renal function can lead to interactions between these and co-administered drugs that also rely on renal elimination.

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