Blog 20- Introduction

The elderly use more medications (including prescription drugs, over-the-counter drugs, dietary supplements) than any other age group.  The appropriate use of medications allows the elderly to manage chronic diseases but brings with it the risk of adverse drug reactions (ADRs).  Learning how drugs are processed in our bodies to produce a specific effect is the first step to appreciate the effects of age and disease on drug use and the origins of ADRs. The second step is to apply this knowledge and avoid adverse drug reactions. Both of these issues will be discussed in this blog and the next.

What Are Adverse Drug Reactions ?

An adverse drug reaction is “an appreciably harmful or unpleasant reaction” that occurs with use of a medicinal product and which requires reevaluation of its use” (Lancet 2000 Oct 7;356(9237):1255-9 http://pubmed ).  ADRs range from mild to severe and life-threatening.  They are definitely unwanted effects.  Unfortunately, ADRs have many causes. 

Reasons for Adverse Drug Reactions in Elderly

ADRs are more severe and frequent in the elderly compared with younger individuals.  Furthermore, ADR severity and frequency increases directly with the number of drugs consumed daily.  As noted above, drug use in the elderly is higher than any other age group.  Reasons for ADRs are numerous.  They include the following:

1.  Age changes alter how drugs are handled in the body

2.  Disease reduces organ function needed to adequately process drugs

3.  Use of multiple drugs has high potential for harmful interactions

4.  Over-the-counter compounds are used inappropriately with prescription drugs  

5.  Inappropriate prescribing by physicians    

Issues 1-4    

Issues 1-4 favor two unwanted outcomes.  Firstly, they influence the concentration of the drug in the blood, causing it to be too high or too low (i.e. outside of the therapeutic window of efficacy).  When a drug’s level is too high, unwanted and possibly life-threatening effects occur and when the drug level is too low, there is no effect and the disease progresses unhindered. Secondly, issues 1-4 also  may hinder a drug’s ability to produce its desired effect, irrespective of drug concentration.  Consequently, when a drug cannot produce its effect, the disease remains untreated. 

Issue 5

Issue 5 relates to taking a drug which is known to exacerbate age-related changes and therefore, should not be prescribed for the elderly.  There exists an extensive list of these drugs, ranging from antispasmodics to antipsychotics (Expert Panel: J Am Geriatr Soc. 67(4):674-694, 2019 http://pubmed).  Unfortunately, many physicians still prescribe them to the elderly.  Issue 5 will be discussed in detail in the following blog.

1.  Age Changes May Influence Adverse Drug Reactions

Principles of pharmacokinetics (PK) and pharmacodynamics (PD) determine how our bodies handle drugs.  Specifically, principles of PK describe absorption of a drug from the GI tract (and other sites), distribution by the circulation to the tissues, metabolism by liver enzymes and excretion by the kidneys.  Principles of PD explain how a drug works at its target site.  In particular, PD explains the ability of a drug to bind to and activate a specific target called a receptor (generally a protein, enzyme or other cell structure) and as a result of these activities, initiates a cascade of subsequent events to produce the predicted therapeutic effect.  Thus PK explains how a drug gets to its target site and PD explains how it works at the target site. 

1a.  In general, effects of age on PK are modest but still important.

Absorption:   

Absorption of drugs, regardless of route (gastrointestinal, intravenous, intramuscular or transdermal), remains stable with age.  Other factors such as disease, and  multiple drugs use alter absorption. 

Distribution: 

Once  absorbed and in the circulation, the distribution of a drug is likely to be influenced by age.  This is because, on average, the elderly have more body fat (20-40% more accumulated over time) and 10% less body water.  With increased body fat, drugs with chemical characteristics of high lipid solubility, e.g. anesthetics and hypnotic-sedative drugs take long to equilibrate (saturate the fat depots) and longer to be eliminated.  This means that it takes a longer time for these drugs to take effect and conversely for their effects to dissipate.  A delay in elimination (of anesthetics) is of concern during major surgery since the delay can result in lower oxygen levels, tissue damage and, possibly, pneumonia.

Metabolism: 

The major site of metabolism of drugs is the liver.  Liver enzymes change the chemical structure of the drug.  This results in assured excretion by the kidneys and termination of the drug’s effect.  Findings from recent studies indicate that with age, even in the absence of disease, detrimental structural changes occur in the liver.  Consequently, age-related reduction in blood flow through the liver and reductions in drug metabolism set up the possibility for drug levels to remain higher than expected for long periods of time.  This can result in ADRs.  A simple blood test that measures key liver enzymes determines liver function.  Hence, reduced liver function requires use of lower drug doses.

Elimination:

The kidneys are the major site of elimination of most drugs  As kidney function declines, drug elimination is impaired, resulting in a higher than required drug level.  Thus, ADRs are likely.  Kidney function may decrease with age.  Structural changes that decrease kidney function in the elderly have been reported.   Therefore, it is important that prior to drug use, kidney function is assessed.  A blood test (usually part of the metabolic panel) measures a value called creatinine which indicates the level of kidney function.  Low kidney function requires use of a lower drug dose.

1b.  Significant PD changes occur with age. 

Drug absorption and distribution assure that a drug arrives at its site of action i.e. the select receptor or enzyme.  The binding of drug with its target site leads to the needed therapeutic effect.  With age, receptors may disappear or change in sensitivity.  Specifically, a class of receptors termed beta-adrenergic receptors diminish in number and responsiveness with age.  Hence, drugs that block these receptors, such as antihypertensives and bronchodilators should be avoided.  Use of antihypertensive drugs in this class would produce serious cardiovascular effects and promote imbalance that may lead to falls.  Additionally, bronchodilators of this class are ineffective in the elderly.  Age-related receptor alterations in the brain also make the use of benzodiazepines (hypnotic-sedative) and antipsychotics of questionable value in the elderly.

2.  Effect of Disease on Adverse Drug Reactions

Disease has the potential to create ADRs.  This is especially true for cardiovascular, liver and kidney disease, since they directly influence distribution, metabolism and elimination of a drug.  As noted above, optimal kidney and liver function are required to metabolize and excrete drugs so as to maintain therapeutic levels.  Kidney and liver disease dramatically alter this.  Therefore, kidney and liver diseases require careful selection of drug and dose.  Additionally, adequate blood flow is also important to assure drugs reach their designated targets.  Cardiovascular disease  reduces blood flow slowing the onset time of drug action and reducing time of offset.

3.  Polypharmacy produces ADRs

Comorbidities of the elderly require multiple drug use.  Use of 4 or more drugs is termed polypharmacy.  It is a significant factor favoring adverse drug reactions (ADRs).  Polypharmacy facilitates ADRs because many drugs use the same liver enzyme for metabolism.  When this happens, the enzymes metabolizes only one drug.  The consequence is that competition for metabolism allows some drugs to remain untouched and so drug levels rise causing toxicities.  Two or more drugs may also compete at the same receptor either in an additive or competitive fashion.  Either way, poor efficacy and ADRs will result. 

Polypharmacy may arise as a result of duplicate medication.  Generally, comorbidities require multiple physicians with different specialties.   If the patient does not fully denote their entire list of medications, physicians may prescribe comparable drugs but with different names.  ADRs are sure to follow.

4.  ADRs with over-the-counter (OTC) products

The combination of  OTCs with prescription medication is problematic.  Firstly, most OTCs are not FDA approved (e.g. have never undergone a controlled clinical trial).  Secondly, quality control of OTCs is unreliable or nonexistent.  Thus, one batch of OTCs may differ radically from another and may also contain contaminants.  Thirdly, the liver metabolizes OTCs, same as prescription drugs and will compete with prescription drug metabolism as noted above.  Thus, OTCs are essentially drugs but without any assurance of amount, efficacy and purity (see Blog 17).  The combination of OTCs with prescription medication is an important topic for discussion with a physician.  Sadly, many elderly do not mention OTC use to their physicians.  The result may be an unnecessary ADR.

Conclusions

There are numerous  causes of adverse drug reactions in the elderly.  Some ADRs result from changes in blood flow, and liver and kidney function due to age and disease. Physicians know this information and should prescribe accordingly. Additionally, ADRs arising from polypharmacy and OTC use should not be surprising.   They too are avoidable but sadly, they still occur.

My next blog will discuss inappropriate prescribing and common sense means to avoid ADRs.