Who needs pharmacogenetic tests?

Seniors, those taking more than 2 medications for pain, heart, kidney, in cancer therapy, anyone who is sensitive to medications/drugs and as prescribed by primary care doctors or specialists (OBs, oncologists, pain docs, pharmacy-based providers).

Doctors have a checklist/panels for pharmacogenetic tests

  • Pain
  • Cardiac
  • Mental health
  • Polypharmacy

 

Aging

Advancing age is characterized by impairment in the function of the many regulatory processes that provide functional integration between cells and organs. Therefore, there may be a failure to maintain homeostasis under conditions of physiological stress. The reduced homeostatic ability affects different regulatory systems in different subjects, thus explaining at least partly the increased interindividual variability occurring as people get older. Important pharmacokinetic and pharmacodynamic changes occur with advancing age. Pharmacokinetic changes include a reduction in renal and hepatic clearance and an increase in volume of distribution of lipid soluble drugs (hence prolongation of elimination half-life) whereas pharmacodynamic changes involve altered (usually increased) sensitivity to several classes of drugs such as anticoagulants, cardiovascular and psychotropic drugs. This review focuses on the main age-related physiological changes affecting different organ systems and their implications for pharmacokinetics and pharmacodynamics of drugs.

Heart

Ageing produces major cardiovascular changes, including reduced elasticity and compliance of the aorta and great arteries [3]. This results in a higher systolic arterial pressure, increased impedance to left ventricular ejection, and subsequent left ventricular hypertrophy and interstitial fibrosis [4]. A decrease in the rate of myocardial relaxation also occurs. The left ventricle becomes stiffer and takes longer to relax and fill in diastole, thus increasing the importance of a properly timed atrial contraction in contributing to a normal left ventricular end-diastolic volume [5]. The isotonic contraction is prolonged and velocity of shortening reduced.

Renal mass decreases with age [10]. This reflects the reduction in nephrons [11]. Intra-renal vascular changes also occur, consisting of hyalinization of the vascular tuft leading to reduced blood flow in the afferent arterioles in the cortex [12]. No changes in the medullary vasculature are reported with ageing [13]. Both renal plasma flow and glomerular filtration rate decline with age. The decline is not uniform or consistent, however, [14, 15]. Despite the decline in glomerular filtration rate, there is no concomitant increase in plasma creatinine because of age-related loss of muscle mass. T.

Liver

Advancing age is associated with a progressive reduction in liver volume and liver blood flow [31]. Alteration of hepatic structure and enzymatic functions with ageing is moderate. In the healthy elderly person, routine tests of liver function involving the metabolism and elimination of specific dyes, radioisotopes, and protein synthesis do not show significant differences between individuals aged 50–69 and 70–89 years

herefore, creatinine is not a reliable indicator of glomerular filtration rate in the elderly subject. Other markers such as serum cystatin C do not provide significant advantages over creatinine for the measurement of creatinine clearance.

Neuroendocrine responses

Ageing is accompanied by changes in neuroendocrine responses to psychosocial or physical stress. In particular, an altered function of the hypothalamic-pituitary-adrenal (HPA) axis has been observed. Excessive HPA activation and hypersecretion of glucocorticoids can lead to dendritic atrophy in neurones in the hippocampus, resulting in learning and memory impairment. Damage or loss of hippocampal neurones results in impaired feedback inhibition of the HPA axis and glucocorticoid secretion, leading to further damage caused by elevated glucocorticoid concentrations. This positive feedback effect on hippocampal neuronal loss is known as the glucocorticoid cascade hypothesis [34]. Thus, glucocorticoids may sensitize hippocampal neurones to cell death and/or functional impairment, indirect effects that are likely to be age-dependent.

First-pass metabolism and bioavailability

Ageing is associated with a reduction in first-pass metabolism. This is probably due to a reduction in liver mass and blood flow [52]. As a result, the bioavailability of drugs undergoing extensive first-pass metabolism such as propranolol and labetalol can be significantly increased [53–55]. On the other hand, several ACE inhibitors such as enalapril and perindopril are pro-drugs and need to be activated in the liver. Therefore, their first-pass activation might be slowed or reduced with advancing age.

Drug distribution

As a consequence of the age-related changes in body composition [36], polar drugs that are mainly water-soluble tend to have smaller volumes of distribution (V) resulting in higher serum levels in older people. Gentamicin, digoxin, ethanol, theophylline, and cimetidine fall into this category [58–60]. Loading doses of digoxin need to be reduced to accommodate these changes [60]. On the other hand, nonpolar compounds tend to be lipid-soluble and so their V increases with age. The main effect of the increased V is a prolongation of half-life. Increased V and t1/2 have been observed for drugs such as diazepam, thiopentone, lignocaine, and chlormethiazole [61–66].

Protein binding

Acidic compounds (diazepam, phenytoin, warfarin, salicylic acid) bind principally to albumin whereas basic drugs (lignocaine, propranolol) bind to α1-acid glycoprotein. Although no substantial age-related changes in the concentrations of both these proteins have been observed [33, 67], albumin is commonly reduced in malnutrition or acute illness whereas α1-acid glycoprotein is increased during acute illness.

Drug clearance

Kidney

Reduction in renal function in elderly subjects, particularly glomerular filtration rate, affects the clearance of many drugs such as water-soluble antibiotics [69, 70], diuretics [71], digoxin [72], water-soluble β-adrenoceptor blockers [73], lithium [74], and nonsteroidal anti-inflammatory drugs [75, 76]. The clinical importance of such reductions of renal excretion is dependent on the likely toxicity of the drug. Drugs with a narrow therapeutic index like aminoglycoside antibiotics, digoxin, and lithium are likely to have serious adverse effects if they accumulate only marginally more than intended. However, a recent study has questioned the importance of age-related reduction in renal function in affecting pharmacokinetics. Although creatinine clearance was slightly reduced in healthy elderly subjects, excretion of atenolol, hydrochlorothiazide and triamterene was similar to young subjects.

Congestive heart failure

Studies investigating possible age-related differences in cardiovascular function in patients with congestive heart failure show a progressive decrease in heart rate and an increase in systemic vascular resistance in older patients [97]. This is associated with increased plasma noradrenaline and serum creatinine concentrations [97]. The therapeutic implications of some pharmacokinetic changes involving the main agents used for the treatment of this condition are discussed.

Digoxin

Digoxin is well absorbed in the gastrointestinal tract. However, the time to peak plasma concentrations is prolonged with advancing age from a mean of 38 h in younger subjects to 69 h in elderly subjects [60]. Therefore, the time to reach steady-state plasma concentrations increases from 7 to 12 days in elderly subjects. The volume of distribution is decreased in elderly patients. As a result, loading doses should be reduced by approximately 20%[60].

Because digoxin is cleared mainly through the kidneys and digoxin clearance is proportional to creatinine clearance [98], the systemic clearance of digoxin is reduced with age [60]. As clearance is the main determinant of the maintenance dose, the daily dose of digoxin should be reduced. This should be guided by renal function and body weight.

Diuretics

Several studies investigated the effect of ageing on the pharmacokinetics of frusemide administered intravenously [99, 100]. The volume of distribution was similar in older subjects as compared with younger individuals. This was associated with a reduced renal clearance and a prolonged half-life in elderly subjects [99, 100]. The reduced effects of frusemide with ageing seem to be due mainly to a decrease in tubular secretion. The latter may be caused by a reduction in renal plasma flow.

A slight reduction in the renal clearance of thiazide diuretics and triamterene, alone or in combination, has also been observed with advancing age [101, 102]. The latter findings have been disproved by a recent study [77].

ACE inhibitors

Some of the drugs of this class are active compounds (i.e. lisinopril) but most are pro-drugs undergoing activation in the liver (i.e. enalapril, perindopril). This biotransformation might be impaired in patients with severe heart failure and hepatic congestion. Most of the ACE inhibitors are excreted through the kidney by glomerular filtration and tubular secretion. In the presence of renal impairment their plasma concentration increases