Category Archives: Adverse Drug Reactions

Inappropriate Medications for the Elderly

Adverse Drug Reactions, Individual controls aging, , ,

Blog 21 –  Adverse Drug Reactions, Part II

Introduction

The prescribing of inappropriate medications for the elderly creates for them an unnecessary burden, physically and financially.  As noted in Blog 20, and further described here, prescribing of potentially inappropriate medications is one of several acknowledged reasons for adverse drug reactions (ADRs) in the older adult.  

ADRs are harmful and potentially life-threatening reactions dependent on medication use.  ADRs require readjustment or stoppage of the medication.  The elderly are especially sensitive to ADRs as a result of age changes that affect many aspects of drug handling by the body, comorbidities and multiple drug use (see Blog 20).  Prescribing of potentially inappropriate medications brings with it needless ADRs.  This blog will define inappropriate medications according to the Beers Criteria.  It will also discuss the importance of this topic and reasonable ways to avoid ADRs.

Potentially Inappropriate Medications – Origins

Slightly more than 30 years ago, JM Beers organized a panel of clinical experts to systematically categorize appropriate and inappropriate medications in nursing homes (Beers et al., 1991).  From this insightful investigation developed the Beers Criteria, a thoughtfully researched  and expertly evaluated presentation of drugs considered as inappropriate medications for the elderly.  Experts update the Beers Criteria every 3 years with the most recent update published in 2019 (see references).

Potentially Inappropriate Medications – Reasons for drug selection

Medications on the Beers Criteria are there for several reasons.  These are medications that

a)  on average should be avoided in the elderly due to data on age changes,

b)  are to be avoided in elderly with certain conditions,

c)  have low efficacy and hence the risks outweigh benefits and for which there are safer and more efficacious drugs,

d)  are known to interact poorly with commonly used essential drugs and

e)  require extremely careful dosing due to kidney disease

As with all advice on drug use, there are additional issues to consider.  Over time “inappropriate medications” on Beers Criteria became “potentially inappropriate medications”.  This recognizes the possibility that some patients may do well (efficacy in the absence of expected ADRs) with a drug considered inappropriate and, therefore, the caregiver/patient are the final arbiters.

Potentially Inappropriate Medications – Specific classes and drugs

Using medication data from Medicare Part D participants, Toth et al., (2022) reported that inappropriate medications prescribed most frequently fell into one of the following classes of drugs:  proton pump  inhibitors, benzodiazepines and antipsychotics.  These frequently prescribed potentially inappropriate medications are detailed below. Additional potential inappropriate medications (partial list) are presented in the schematic at the end of the blog.  

Proton Pump Inhibitors

Drugs classified as proton pump inhibitors act by blocking acid secretion in the stomach.  Thus, these drugs are useful in the treatment of acid-related disorders e.g. peptic ulcer, gastric reflux.  Drugs in this class are inappropriate for the elderly for several reasons:  Firstly, chronic use is associated with increased risk of bone loss. This would add to the presence of reduced bone density, common in the elderly.  As bone density decreases, the risk of fracture increases.  Fractures are costly, both financially and physically, limiting mobility and independence. Secondly, chronic acid suppression allows for overgrowth of harmful bacteria and use of proton pump inhibitors is associated with the onset of Clostridium difficile infection, a severe bacterial infection that is difficult to eliminate.  Omeprazole (Prilosec) is a proton pump inhibitor that is frequently prescribed.

Benzodiazepines

Drugs labeled benzodiazepines act in the brain to reduce anxiety and induce sedation.  As such they are anxiolytic and hypnotic drugs.  These drugs are inappropriate in the elderly because they hinder memory and additionally are associated with an increased risk of falls. Reduction of memory at any age is unwanted.    Increased risk of falls is highly associated with a fracture with serious consequences.  Additionally, these drugs are addictive.  Commonly prescribed benzodiazepines are alprazolam (Xanax), and lorazepam (Ativan),

Antipsychotics

Antipsychotics act on the brain to suppress psychosis.  These drugs are also sedating and associated with onset of abnormal muscles twitching.  Their use is inappropriate in psychosis associated with Parkinson’s Disease as they exacerbate the disease-dependent muscular dysfunction.  They are also inappropriate in individuals with dementia or cognitive impairment.  Since these drugs are sedating, they are inappropriate in individuals with a history of falls.  Commonly prescribed antipsychotics are quetiapine (Seroquel) and risperidone (Respirdal).

Future Steps

The prevalence of exposure in the elderly to potentially inappropriate medications varies between ~14% to 41% or more depending on the population under study.  Fortunately, the prevalence of prescribing potentially inappropriate medications has declined a few percentage points from 2013 to 2019 (Clark et al., 2020).  This is an encouraging start.  Additionally, there is effort by the medical community to  educate physicians, pharmacists, all prescribing care givers and patients on this issue.  This should further reduce prescribing of potentially inappropriate medications.

Common Sense Approach to Avoidance of ADRs

  • Non pharmacological interventions should always be tried first (see Blogs 2,3,10,11).  Interventions e.g. exercise and diet are highly successful strategies to prevent and moderate diseases such as Type II  diabetes, hypertension (high blood pressure), and heart disease.
  • Older adults taking medications should establish clear goals and endpoints with their physician and continually re-evaluate them.  Every patient needs to know exactly why the medication is prescribed and what to expect from it, that is, how to know if it is working and therefore, worth taking. 
  • It is important to reduce polypharmacy (simultaneous use of more than 4 medications).  The higher the number of prescribed drugs, the greater the risk for ADRs.  Each patient and physician should review drugs frequently and endeavor to eliminate duplicates, and potentially inappropriate medications and keep only the essential drugs.
  • In reduction of polypharmacy, the usage of some drugs is terminated.  Drug withdrawal should be a serious undertaking.  Dose reduction should always be as slow as possible, extending over weeks and months, thereby avoiding unnecessary ADRs.
  • The actual drug dose is critical to avoiding ADRs.  It is common sense to start with the lowest dose possible and increase slowly, if at all.  The use of higher doses requires convincing justification.
Some Additional Potentially Inappropriate Medications

Conclusions

Based on Beers Criteria, an updated assessment of potentially inappropriate medications for the elderly is available to prescribing caregivers and pharmacists.  Drugs on this list negatively interact with age changes in the elderly and hence are potentially inappropriate medications and are responsible for ADRs.  ADRs can be avoided if physicians as well as the patients are informed about the main causes of ADRs and how to prevent them.

References

2019 American Geriatrics Society Beers Criteria Update Expert Panel.   American Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults.  J Am Geriatr Soc. 67(4):674-694, 2019.

Beers et al., Explicit criteria for determining inappropriate medication use in nursing home residents. UCLA Division of Geriatric Medicine Arch Intern Med.  151(9):1825-32, 1991.

Clark CM et al., Potentially Inappropriate Medications Are Associated with Increased Healthcare Utilization and Costs. J Am Geriatr Soc 68(11): 2542–2550, 2020.

Croke L. Beers Criteria for inappropriate mediation use in older patients: An update from the AGS. Am Fam Physician. 101(1):56-57, 2020.

Fernandes de Oliveira RMA et al., Potentially inappropriate medication use in hospitalized elderly patients. Rev Assoc Med Bras 68(6): 797-801, 2022.

Fralick M et al., Estimating the Use of Potentially Inappropriate Medications Among Older Adults in the United States. J Am Geriatr Soc. 68(12):2927-2930, 2020.

Toth JM et al., Prescribing trends of proton pump inhibitors, antipsychotics and benzodiazepines of Medicare part d providers. BMC Geriatrics  22:306-321, 2022.

Steinman MA. How to Use the AGS 2015 Beers Criteria – A Guide for Patients, Clinicians, Health Systems, and Payors.  J Am Geriatr Soc. 63(12): e1–e7, 2015..

Drug Use In The Elderly: Adverse Drug Reactions

Adverse Drug Reactions, Individual controls aging, , , ,

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. 

How drugs are handled in the body

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.

Summary: Age and disease influence how drugs are handled in the body

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.

Potential Causes of Adverse Drug Reactions

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.