After absorption, how a drug is distributed within the body compartments depends upon its lipid and water solubility and the extent to which it is bound to plasma proteins. The volume of distribution (Vd) is the pharmacokinetic variable that relates the drug dose administered to its resulting concentration in body fluids. Aging decreases the body’s lean-to-fat ratio and total body water 10–15 % by age 80 [6]. Subsequently, this results in a reduced Vd for water-soluble drugs and those drugs distributed to lean body tissues. Therefore a reduced loading dose is recommended for water-soluble medications such as digoxin, lithium, and theophylline. Conversely, the age-related increase in body fat content increases the Vd for lipid-soluble medications such as benzodiazepines, amiodarone, and hormones (thyroid), thereby resulting in reduced clearance and elimination time from the body.

Albumin and alpha-1-acid glycoprotein are the most common plasma proteins to which many drugs are bound. Although the concentrations of these plasma proteins do not normally decline significantly with normal aging, reduced nutritional status or catabolic states may cause a clinically important decline. Medications that are highly protein-bound, such as the warfarin and phenytoin, will have higher free serum concentrations in the elderly who have reduced plasma proteins [7]. For example, a patient may have a low total phenytoin blood level in the presence of hypoalbuminemia, yet a normal therapeutic free phenytoin level. So in order to avoid phenytoin toxicity, dose adjustments may need to be based on free dilantin level, not on the total blood level.

Liver mass and blood flow decrease significantly with aging, reducing clearance and increasing the half-life and bioavailability of medications that undergo extensive first-pass metabolism such as propanolol and labetolol [5]. On the other hand, the bioavailability of several ACE inhibitors, such as enalapril and perindopril, is reduced with advancing age because they require hepatic activation [8]. The activity of the hepatic cytochrome P450 oxidase system diminishes with age, including many Phase I reactions (reduction, oxidation, hydroxylation, and demethylation). Table 1 summarizes important isoenzymes of the P450 cytochrome system and commonly prescribed drugs whose metabolism is affected by them. Of note, grapefruit juice is a known inhibitor of the cytochrome P450 3A4 pathway. Such inhibitors can decrease clearance, increase half-life, and thus increase toxicity of some drugs [9]. Phase II reactions (drug conjugation with glucuronide and sulfate and drug acetylation) are minimally influenced by aging.

Decreased renal elimination is the most significant pharmacokinetic change seen in the geriatric population. In one study of 10,000 long-term care residents, 40 % had significant renal insufficiency [10]. Renal mass decreases an average of 20 % from the fourth to the eighth decades of life with concomitant age-associated reductions in glomerular filtration rate, renal blood flow, and tubular secretion. Thus drugs that depend upon renal clearance require a dosage reduction [11].

With decreased muscle mass in the geriatric population, serum creatinine by itself is not an accurate measure of renal function. Calculators based on equations such as the Cockcroft–Gault Equation , that take into account a patient’s measured serum creatinine, sex, age, and estimated lean body weight, give a more accurate approximation of creatinine clearance [12]. Another method to estimate creatinine clearance, the Modification of Diet in Renal Disease (MDRD) equation , can be used in clinical practice but is not yet recommended for adjustment of medication doses in the elderly nor routinely used in drug information sources and drug labeling on dosage recommendations [13].

Pharmacodynamics is the interaction between a drug and its effector organ(s) (i.e., receptor) that results in either a therapeutic or adverse response or both. In addition the elderly can exhibit increased sensitivity to the therapeutic as well as the toxic effects of many medications due to comorbid illness such as Alzheimer’s disease, Parkinson’s disease, strokes, congestive heart failure, and other disorders that increase frailty and reduce the ability of the body to maintain homeostasis. Figure 2 lists some pharmacodynamic changes commonly seen in the elderly.

A consensus panel of experts established the Beers’ criteria . This is a list of medications best avoided in the elderly due to the high likelihood of potential adverse effects that has subsequently been included in State surveys of LTCFs. The Beers’criteria include medications with anticholinergic effects such as antihistamines (diphenhydramine) and antiemetics (promethazine), and other medications with a propensity to cause worsening mental status, (i.e., delirium), falls, urinary retention, orthostatic hypotension, dehydration, and movement disorders such as extrapyramidal signs and tardive dyskinesia. Benzodiazepines are also included because they increase the risk of a change in mental status, sedation, and falls [14].

A more recent screening tool, the STOPP (Screening Tool of Older Person’s Prescriptions) , may be more user-friendly than the Beers’ list. A recent systematic review found it to be a more sensitive measure of potentially inappropriate prescribing patterns in community-dwelling, acute and long-term care older patients in Europe, Asia and North America. The STOPP tool was developed as many clinicians considered that certain drugs designated as inappropriate by the Beers’ criteria were debatable, and could be prescribed in certain specific clinical situations. The STOPP criteria were designed to incorporate commonly encountered prescribing pitfalls that practitioners often encounter.

Both the Beers’ and STOPP criteria do not substitute for thorough clinical assessment and good judgment, as clinicians must first and foremost consider whether medications are the possible cause of signs and symptoms seen in older adults. By optimizing and minimizing medication use in the elderly, unnecessary and potentially harmful adverse side effects and prescribing cascades (use of medication to treat the side effects of another) can be lessened or avoided. The STOPP criteria are summarized in Table 2 including examples of potential adverse outcomes due to inappropriate prescribing [15].