Drug Metabolism and AgingRuslan Dorfman
Optimizing medications for older patients
Prescribing for older patients can be challenging. Studies have shown that the elderly are more unpredictable in their response to both the benefits and adverse effects of medications.
There are many biological processes that determine how the body reacts to a drug and each of these processes are affected by aging in various ways. Once a drug, or vitamin, enters the body, it undergoes Absorption, Distribution, Metabolism, and Excretion – or ADME. ADME is a pharmaceutical term used to describe what your body does to a drug. Inherited variations in drug metabolic genes can have a strong impact on the efficacy and side effects of medications. Pharmacogenetics can help reduce the risk of adverse reactions.
ADME and Aging in a Nutshell
Absorption refers to the entry of a drug into the bloodstream from the site of administration (i.e. oral, injection, inhalation). A drug taken orally will usually enter the bloodstream from the intestines. The nature of the drug determines how easily it is absorbed. For example, acidic drugs like aspirin are better absorbed in the stomach and basic drugs like morphine are better absorbed in the lower parts of the gastrointestinal (GI) tract. Ever wondered why you are required to take some medications with a meal? For some drugs, the amount of acid or food in the stomach really impacts how that drug is absorbed. Generally, most drug absorption happens in the small intestine since there is a much greater surface available than the stomach.
Aging affects the intestinal track. Aging intestinal cells have decreased absorption and this can impact how rapidly a drug enters the bloodstream in older individuals. However, there is little evidence showing that the overall absorption of a drug changes with age. In aging individuals, changes in absorption do not seem to be as significant as changes in the distribution of the drug. Individuals may also have inherited variations in drug absorbing genes that combined with age-related reduction in drug absorption would have even stronger impact in older people.
Distribution refers to the movement of a drug in the bloodstream to the site in the body where it takes action. Blood flow to tissues, and the ability of a drug to enter the vascular system or cells of the tissue, affect distribution.
After a drug is absorbed by the GI tract, it is taken to the liver (via the hepatic portal system) for delivery to the bloodstream, or in some cases the lymphatic system if the drug is a lipid. Drugs that are water-soluble have an easier time traveling in the bloodstream than drugs that are not water-soluble. Non-water-soluble drugs need to bind to a carrier protein before they can be transported via blood. Depending on the drug, different carrier proteins are required. Acidic drugs bind to the carrier protein albumin and basic drugs bind to a carrier protein called α1 – acid glycoprotein.
As we age, the amount of albumin decreases while the amount of alpha-1 glycoprotein increases. This needs to be taken into consideration when prescribing for older individuals. Older individuals also tend to have a greater percentage of body fat and decreased total body water. Decreased body water means less volume of distribution for water-soluble drugs and increased body fat means more volume of distribution for fat-soluble drugs. Combined with other age-related changes in the body, changes in drug distribution can have a profound effect on overall concentration of a drug in the body.
Since drugs are foreign substances, they eventually need to be excreted. Metabolism refers to the chemical changes a drug goes through in the body that allows that drug to exit, often in urine via the kidneys or in bile via the intestinal tract. If going through the kidneys, drugs are converted into a form that is more water-soluble. Metabolism occurs mainly in the liver and kidneys. Sometimes, after metabolism, the drug will be converted into a form that is more active. An example of this is anxiolytic benzodiazepine.
Of all the changes that occur with aging, changes to the liver can have the greatest impact on drug response in older individuals.
Age-related changes to the liver include a decrease in liver mass and decreased blood flow to the liver (hepatic blood flow). Studies using imaging techniques have shown that both liver mass and liver blood flow can decrease 40% in the elderly. Drugs that rely on blood flow to the liver for exiting the body would have increased bioavailability – or ‘the amount of drug available to the body’ – and dosages would need to be lowered. Examples of these drugs include acetaminophen, antiarrhymics, anticonvulsants, antidepressants, antipsychotics, benzodiazepines, warfarin, and some beta blockers. In some individuals, inherited reduced drug metabolism will be exacerbated by aging, or liver diseases.
Excretion is the removal of a drug, usually in urine or bile, although some drugs leave the body through sweat, saliva, tears or breath. Any problems with the kidneys or liver can lead to increased levels of a drug in the body. Like the liver, the kidneys also decrease in mass with age. A 10-20% reduction of kidney mass occurs between the ages of 40-80. Dosage adjustments may be required for drugs that are eliminated through the kidneys. These drugs include: allopurinol, most antibiotics, lithium, and quinidine.
How does aging impact Pharmacogenomics?
Pharmacogenomics looks at how genetic differences in liver enzymes affect how those enzymes metabolize medications. The liver enzymes responsible for the metabolism of medications tend to belong to the cytochrome family of enzymes (CYPs). Depending on genetic differences, some people can be poor metabolizers (PM), and others intermediate metabolizers (IM), extensive metabolizers (EM) or ultrafast metabolizers (UM).
The effect of aging on CYPs can vary, as aging has been shown to reduce the activity of some but not all CYPs.
One study looking at the drug omeprazole in people with three different CYP2C19 metabolizer statuses (poor, intermediate, and extensive metabolizers) observed higher bloodstream concentrations of omeprazole in older individuals who were extensive and intermediate metabolizers but not in poor metabolizers.
A different study, found no impact of aging in young and elderly individuals of different CYP2C9 metabolizer statuses. The drugs investigated in the study were diclofenac and celecoxib, both of which are metabolized by CYP2C9.
Warfarin is another drug that was studied to see if aging impacted genetic variations in CYP2C9 and VKORC1 differently (the two genes that together can determine more than 60% of the variability in warfarin response between different people). This study found that genetics had a greater impact in younger individuals. Older individuals required a dose decrease of 0.2 mg per decade regardless of CYP2C9 and VKORC1 metabolizer status.
These studies show that aging can affect liver enzymes differently and that more studies are needed to investigate how various drugs are impacted in the elderly.
With the large number of age-related factors that influence drug response, increased monitoring by a physician is always advised. A Pillcheck test can determine additional precautions when prescribing medications for older patients. Pillcheck currently predicts drug response for 139 medications.
Contribution of age, body weight, and CYP2C9 and VKORC1 genotype to the anticoagulant response to warfarin: proposal for a new dosing regimen in Chinese patients. Miao L, et al. European Journal of Clinical Pharmacology. 2007: Volume 63, p1135-1141.