Over 5.7 million patients are admitted to the ICU each year.1 The number of patients over age 65 who are admitted to the ICU is two to three times greater than those under age 65.2 Over 60% of days in the ICU were experienced by adults over age 65.3,4
One challenge of caring for older adults in the ICU is the management of complex pharmacotherapy for the primary admitting critical diagnosis, in addition to polypharmacy for multiple preexisting chronic illnesses.5 One study of more than 2,300 adults (ages 62 to 85) suggested that 87% take at least one prescription drug and 29% take 5 or more.6 Another important challenge is considering how the normal physiologic changes associated with aging may affect drug therapy.
Age as a risk factor
Age can be a risk factor for complications of drug therapy. Glucocorticoids administered for acute respiratory distress syndrome, septic shock, and exacerbation of chronic obstructive pulmonary disease can cause delirium or other adverse neurologic events.7
Select physiologic changes associated with aging can alter the pharmacokinetic and pharmacodynamic properties of drugs as well as increase patient vulnerability specific to pharmacotherapy. Older adults must be evaluated for polypharmacy and use of high-risk drugs, including opioids, sedatives, hypnotics, vasoactive agents, and drugs that can adversely affect organ function. In addition, older adults may be more sensitive to the therapeutic effects of certain drugs, such as benzodiazepines and opioids.6
Aging, pharmacokinetics, and pharmacodynamics
Several factors affect pharmacokinetics in critically ill older adults, including the normal physiologic changes of aging, such as decreased liver and kidney function. See Key terms. Disorders highly prevalent in the ICU, such as acute kidney injury (AKI), systemic inflammatory response syndrome (SIRS), and sepsis, put the critically ill older adult at risk for pharmacokinetic changes. For example, drug concentrations will decrease as the volume of distribution increases related to presence of SIRS, edema, or administration of I.V. fluids or medications that enhance contractility (inotropes, such as dopamine).10 Presence of any condition that causes hypotension will affect the absorption, metabolism, and excretion of drugs because of decreased perfusion to body areas that impact these functions.
Older adults are at risk for drug interactions from complex drug regimens used to treat critical illness and presence of multiple organ dysfunction, which can alter pharmacokinetic and pharmacodynamic drug properties because of decreased rates of drug metabolism and excretion.10,11
Absorption. Several age-related factors can affect drug absorption, including changes in gastric pH, gastrointestinal (GI) motility, and GI tract perfusion (including hepatic blood flow). For example, absorption of aspirin may be compromised in the presence of increased gastric pH.12 Similarly, if drugs require food to be adequately absorbed and the patient has poor nutritional status, drug absorption will be decreased. Age-related changes in skin and in total and regional fat distribution can affect the absorption of topically administered drugs, such as nitroglycerin.9 Absorption of topical agents is based on blood flow to the skin. As blood flow to the skin is increased in obesity, the absorption of topical nitroglycerin will increase. Age-related decreases in cardiac output may also affect the absorption of drugs administered subcutaneously, such as insulin or heparin, or I.M., such as epinephrine for hypersensitivity reactions. For these reasons, alternative administration routes may need to be considered when caring for older adults in the ICU.13
With these age-related changes in mind, there are some studies that suggest that the effect of vasopressors (dopamine, norepinephrine, epinephrine) may decrease the absorption of orally or subcutaneously administered drugs.14 For example, there are limited data to suggest that subcutaneous administration of heparin for prevention of venous thromboembolism may result in a decreased anticoagulant effect in the presence of vasopressor therapy.14
Age-related changes can also affect the absorption of drugs that undergo first-pass metabolism. For example, the absorption of nitrates and lipophilic beta-blockers such as metoprolol and carvedilol may be decreased.5
Distribution. Age-related factors can affect distribution of drugs, such as decreases in total body water and muscle mass, and increases in fat.5,9 Age-related hypoalbuminemia will also impact drug distribution. Hypoalbuminemia can result from protein catabolism associated with trauma or stress and from increased vascular permeability, which is often seen in sepsis and burns.13,15 If an older adult is given a drug that is highly protein-bound, there will be less protein binding, resulting in increased amounts of the drug left unbound. This means that patients will have higher concentrations of the circulating drug, which may result in increased drug toxicities.16 Examples of highly protein-bound drugs include phenytoin and other antiepileptic drugs. Patients may develop toxic effects from phenytoin when hypoalbuminemia is present.15 This same effect can be seen with antibiotic therapy (ceftriaxone, aztreonam, daptomycin).10 Similarly, sedative levels (such as midazolam) may be affected by hypoalbuminemia.17
Aging is associated with a decrease in adipose tissue function; as a result, drug clearance is delayed, exposing the patient to the drug for a longer period of time (for example, most psychotropic drugs).18,19 Other drugs used in the ICU with plasma-binding implications include haloperidol, fentanyl, lidocaine, nicardipine, and propofol.14 Decreases in total body water from aging may result in decreased distribution of water-soluble drugs, such as atenolol.9 Similarly, drugs that distribute well into muscle may not distribute well to older adults with decreased muscle mass.5 The decreased muscle mass associated with aging may be caused by decreased activity, inadequate intake of protein and calories, or decreases in some hormone concentration (for example, growth hormone).
Alterations in tissue perfusion, commonly seen in critically ill older adults, can decrease delivery of hydrophilic drugs. The decrease in tissue perfusion can affect drug effectiveness in peripheral tissues and noncore organs. For example, a decrease in distribution of piperacillin into skeletal muscles and subcutaneous adipose tissue in patients with septic shock has been reported.20
Critically ill older adults with sepsis often develop third spacing from release of proinflammatory mediators, which changes the volume of distribution and the relationship between drug dose and serum concentration, specifically impacting hydrophilic drugs, such as aminoglycosides and beta-lactams.10
Metabolism. The main factors that affect metabolism of medications are age-related hepatic changes, such as decreased liver size and hepatic perfusion. Decreased liver metabolism related to aging will affect drugs such as morphine sulfate, amlodipine, diltiazem, lidocaine, verapamil, warfarin, and alprazolam.20 Slowing of metabolism results in increased drug effect since it remains in the circulation longer. This can predispose the patient to an increased risk of drug toxicity.
Hepatic blood flow can also be decreased by drugs frequently used in the ICU, such as vasopressors, including norepinephrine and epinephrine. Metabolism of drugs such as midazolam and fentanyl will be decreased by hepatic hypoperfusion. When hepatic blood flow decreases, as with septic shock, drug metabolism will also decrease.14
Age-related reduced function of the hepatic cytochrome P450 (CYP) enzyme system will decrease the metabolism of hepatically metabolized medications, predisposing the patient to toxicities from prolonged drug exposure. One of the most important enzyme systems for drug metabolism is the CYP3A4. Some common ICU drugs affected by CYP3A4 include calcium channel blockers (diltiazem, verapamil, amlodipine), benzodiazepines (midazolam, alprazolam), opioids (fentanyl), antipsychotics (haloperidol), antiarrhythmics (lidocaine, amiodarone), warfarin, glucocorticoids (hydrocortisone, dexamethasone), and phenytoin.20
Excretion. Drug excretion is primarily accomplished by the kidneys. Age-related changes in kidney function include decreased renal perfusion and size of the kidneys, with an associated decrease in number of functioning nephrons. Aging also results in a decreased glomerular filtration rate (GFR), which will slow drug elimination. Changes in kidney function are considered one of the most significant pharmacokinetic changes related to aging.15 Age-related alterations in kidney function can slow the elimination of medications, putting the patient at risk for increased medication exposure and associated toxicities.5,20
Older patients with increases in body fat may have decreased elimination of fat-soluble medications.5 In the ICU, the normal physiologic changes associated with aging will decrease renal excretion of drugs, including morphine, oxycodone, amikacin, ciprofloxacin, gentamicin, levofloxacin, captopril, enalapril, digoxin, heparin, lisinopril, procainamide, hydrochlorothiazide, and ranitidine.21
When renal clearance of drugs is decreased, drug elimination half-life increases. Adjustments in dosage are indicated.22
Implications associated with changes in pharmacodynamics in critically ill older adults include increased drug responses, increased risk of adverse drug events (ADEs), and increased drug-drug interactions (DDIs).
Age-related changes can affect the sensitivity of a patient to a drug. Older adults have an amplified reaction to drugs that affect the central nervous system (CNS) and cardiovascular system. The augmented effect may be due to age-related decreases in CNS function. Older age is also associated with a decrease in response to some cardiovascular medications due to changes in sensitivity of cardiovascular receptors.23
As changes in receptor sites occur, a decrease in effectiveness of some drugs (beta-agonists, beta-blockers) can be anticipated. Variability in response to vasopressors has also been reported; age and variable end-organ sensitivity contribute to response variability.24 When these agents are administered in older adults, careful titration and monitoring of effects is essential. Older adults receiving antihypertensive agents may develop hypotension and orthostasis.5 Similarly, renal toxicity from nephrotoxic medications is another pharmacodynamic effect associated with aging, especially those with preexisting renal dysfunction.
Other examples of changes in pharmacodynamics include effects of anticholinergic agents and antihistamines, which can result in urinary retention. Altered effects of antihypertensive agents (alpha-adrenergic blockers) and anticoagulants should also be anticipated given age-related changes resulting in increased drug sensitivity.5 Drug sensitivity refers to the ability of a person, “relative to the abilities of others, to respond in a qualitatively normal fashion to a particular drug dose.”25 Patients may not be able to tolerate adverse reactions of a medication even when administered at therapeutic levels or below.
Adverse drug events. ADEs are more likely to occur in the ICU for many reasons, including complex drug regimens, comorbidities, high drug dosages, polypharmacy, high-alert medications such as anticoagulants and insulin, and multiple organ dysfunction.10 ADEs are more likely to occur in older adults because of age-related changes affecting all four components of pharmacokinetics. Disorders such as heart failure, hepatic dysfunction, and AKI are more common in older adults and increase the risk of ADEs. Older adults with disorders that decrease hepatic perfusion can decrease drug metabolism and can put them at risk for ADEs.26
Medications prescribed for older adults in the ICU that are most often linked to ADEs include ACE inhibitors, digitalis, and hypoglycemic agents.19 Use caution when administering ACE inhibitors to older adults with decreased GFR. Similarly, low-molecular-weight heparin is associated with excessive bleeding when administered to older adults with decreased GFR.21
Antihypertensives. Physiologic changes associated with aging (for example, decreased baroreceptor function) put older adults at risk for orthostasis. Administration of antihypertensive agents can result in hypotension and places older adults at increased risk for falls and injury.
Psychotropic drugs. Age-related changes also put older adults at risk for ADEs associated with administration of psychotropic drugs. Receptor site changes, decreased neurotransmitter function, and altered renal and liver function put these patients at increased risk.26 Psychotropic drugs that are typically prescribed in the ICU setting include zolpidem, lorazepam, and other benzodiazepines; selective serotonin reuptake inhibitors; and haloperidol.
Drug-drug interactions. Care of the critically ill older adult often requires complex pharmacotherapy, putting the patient at risk for DDIs, which can affect the patient's response to medications.27 Any patient receiving more than one drug (essentially all patients in the ICU) is at risk for a DDI.
Pharmacotherapy for critically ill older adults has several implications for nursing practice (see Nursing implications). Management of these patients is challenging and requires knowledge of the normal physiologic changes associated with aging and how these changes affect pharmacotherapy (see BEERS Criteria). Poor patient outcomes can result when pharmacokinetic and pharmacodynamic goals are not met.30
Pharmacokinetics—The term pharmacokinetics refers to how the body responds to a drug or what the body does to a drug. There are four components to pharmacokinetics—absorption, distribution, metabolism, and excretion.8
Absorption—Absorption is the first step in pharmacokinetics. It occurs when the medication goes from the route of administration into the patient's bloodstream.9
Distribution—Distribution is the second phase of pharmacokinetics. It happens once the medication has been absorbed into the body and is circulated from the bloodstream to the tissues of the body, where its therapeutic effect can be exerted. There is a positive relationship between distribution and perfusion; the higher the perfusion or blood flow to an organ, the greater the amount of medication delivered to that organ.9
Metabolism—Metabolism is the third phase of pharmacokinetics. It involves the metabolic breakdown of the medication. Most drug metabolism occurs in the liver.9
Excretion—Excretion is the final phase of pharmacokinetics. It involves removing the medication from the body. This is primarily accomplished by the kidneys.9
Check it out online! Visit www.nursingcriticalcare.com to see animations illustrating absorption, distribution, drug binding, and excretion.
- Monitor peak and trough levels of nephrotoxic drugs (for example, aminoglycoside or vancomycin).
- If absorption of drugs by the oral or subcutaneous route is questionable, precise monitoring for effectiveness of therapy is indicated.
- Monitoring of drug levels is suggested in patients with hypoalbuminemia when drugs that bind to albumin are administered. Monitor hepatic and renal function results.
- Because there is an associated decrease in muscle mass in older adults, serum creatinine levels may not be the best indicator of renal function; monitoring of creatinine clearance is recommended.
- In patients with sepsis or other disorders that cause third spacing, when the volume of distribution increases, consider monitoring drug levels as drug concentration may be increased.
Alternatively, antimicrobial concentrations may be decreased because of increased volume of distribution and augmented renal clearance provoked by SIRS, capillary leak, decreased protein binding, and administration of I.V. fluids and inotropes.
- Because older adults are at risk for increased sensitivity to some drugs, when initiating new therapy, it is recommended to start at a lower dose and titrate up slowly as indicated.
- A decrease in dosage is recommended when administering drugs that have minimal or no binding to albumin.
- When administering medications via a nasogastric tube in patients receiving enteral feedings, consider that drugs may adhere to the lining of the tubing. Flush tubing before and after medication administration.
- When patients are receiving enteral feedings, gastric pH may increase making it an alkalotic environment. Of further note, some medications have decreased absorption in an acidic environment.
For example, phenytoin and ciprofloxacin have decreased rates of absorption when administered with enteral feedings. It is suggested that the enteral feedings be held for 1 to 2 hours before and after administration of such drugs. This will significantly decrease caloric intake. I.V. administration of such drugs is also suggested.
Distribution, metabolism, and excretion
- Consider the impact of the physiologic effects of aging when administering drugs to critically ill older adults.
Metabolism and excretion
- As renal and hepatic blood flow decrease with age, the duration of action of drugs is likely to increase. This puts the patient at risk for increased drug toxicities.
Adverse drug events (ADEs)
- Older adults have increased sensitivity to central nervous system (CNS) depressants and analgesics.
- Monitor for ADEs.
- Refer to BEERS criteria when administering drugs to critically ill older adults. BEERS lists drugs that are possibly inappropriate for older adults.
- Avoid anticholinergics, opioids, nonsteroidal anti-inflammatory drugs, and benzodiazepines or use with caution in critically ill older adults.
Drug-drug interactions (DDIs)
- The cognitive decline associated with the aging process places the patient at risk for poor adherence to their drug regimens.
- To help assure medication adherence, provide education in a manner that can be easily understood by the patient.
- Given the limited data on decreased subcutaneous absorption of low-molecular-weight heparin and questionable efficacy in patients receiving vasopressors, collaborate with the multidisciplinary team and suggest changing the route of administration to I.V.
- Promote evidence-based care and collaborate with the multidisciplinary team to advocate for the older critically ill adult by translating research into practice.
- Be aware of effects of polypharmacy in older adults. Advocate for safe discontinuation of drugs that are no longer essential.
- Collaborate with the ICU provider to determine if dose reductions are indicated in the setting of renal or hepatic dysfunction.
The BEERS Criteria for Potentially Inappropriate Medication Use in Older Adults are evidence-based guidelines presented by the American Geriatrics Society. They list drugs that may cause harm if they are administered to older adults and should therefore be avoided or have dose adjustments based on renal function and potential DDIs.
The updated 2015 guidelines can be viewed at www.guideline.gov/summaries/summary/49933/american-geriatrics-society-2015-updated-beers-criteria-for-potentially-inappropriate-medication-use-in-older-adults.
2. Bell L. The epidemiology of acute and critical illness in older adults. Crit Care Nurs Clin North Am
4. El Said SMS. Geriatrics intensive care unit: outcome and risk factors for in hospital mortality. Adv Aging Res
5. Wooten JM. Pharmacotherapy
considerations in elderly adults. South Med J
6. Qato DM, Wilder J, Schumm LP, Gillet V, Alexander GC. Changes in prescription and over-the-counter medication and dietary supplement use among older adults in the United States, 2005 vs 2011. JAMA Intern Med
7. Lavan AH, Gallagher P. Predicting risk of adverse drug reactions in older adults. Ther Adv Drug Saf
8. Corrie K, Hardman JG. Mechanisms of drug interactions: pharmacodynamics
. Anaesth Intensive Care Med
9. Kaplow R. Oncologic issues in the older adult in critical care. Crit Care Nurs Clin North Am
10. Blot SI, Pea F, Lipman J. The effect of pathophysiology on pharmacokinetics
in the critically ill patient—concepts appraised by the example of antimicrobial agents. Adv Drug Deliv Rev
11. Kämmerer W. Clinically relevant pharmacokinetic drug interactions in the intensive care unit: an overview. Med Klin Intensivmed Notfmed
12. Edmunds MW, Mayhew MS. Aspirin and nonsteroidal anti-inflammatory medications. In: Edmunds MW, Mayhew MS, eds. Pharmacology for the Primary Care Provider
. 4th ed. St. Louis, MO: Elsevier; 2014:403–411.
13. Kruer RM, Jarrell AS, Latif A. Reducing medication errors in critical care: a multimodal approach. Clin Pharmacol
14. Smith BS, Yogaratnam D, Levasseur-Franklin KE, Forni A, Fong J. Introduction to drug pharmacokinetics
in the critically ill patient. Chest
15. Aguayo-Becerra OA, Torres-Garibay C, Macías-Amezcua MD, et al Serum albumin level as a risk factor for mortality in burn patients. Clinics (Sao Paulo)
16. Feghali M, Venkataramanan R, Caritis S. Pharmacokinetics
of drugs in pregnancy. Semin Perinatol
17. Ersoy A, Kara D, Ervatan Z, Çakırgöz M, Kıran Ö. Sedation in hypoalbuminemic geriatric patients under spinal anesthesia in hip surgery. Midazolam or Propofol. Saudi Med J
18. Palmer AK, Kirkland JL. Aging and adipose tissue: potential interventions for diabetes and regenerative medicine. Exp Gerontol
21. Palleria C, Di Paolo A, Giofrè C, et al Pharmacokinetic drug-drug interaction and their implication in clinical management. J Res Med Sci
22. Diasio RB. Principles of drug therapy. In: Goldman L, Schafer AI, eds. Goldman-Cecil Medicine
. 25th ed. Philadelphia, PA: Elsevier; 2016:124–132.
23. Ferrara N, Komici K, Corbi G, et al β-adrenergic receptor responsiveness in aging heart and clinical implications. Front Physiol
26. Galli TB, Reis WC, Andrzejevski VM. Potentially inappropriate prescribing and the risk of adverse drug reactions in critically ill older adults. Pharm Pract (Granada)
27. Alomar MJ. Factors affecting the development of adverse drug reactions (Review article). Saudi Pharm J
28. American Geriatrics Society. American Geriatrics Society 2015 updated Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc
29. Ratanawongsa N, Karter AJ, Parker MM, et al Communication and medication refill adherence: the diabetes study of Northern California. JAMA Intern Med
30. Ruby CM, Nolin TD. Geriatric pharmacotherapy
. In: Robnett RH, Chop W, eds. Gerontology for the Health Care Professional
. Burlington, MA: Jones & Bartlett Learning; 2013.