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Home > Self-Assessment Answers: Pharmacodynamics of Aging

Self-Assessment Answers: Pharmacodynamics of Aging

Question 1:
Define multimorbidity as it relates to older patients.

Answer: Older individuals often suffer from multiple concurrent diseases (e.g. heart disease, diabetes), which often require separate treatments.  Multimorbidity, defined as the presence of two or more chronic conditions, affects more than two-thirds of Americans ≥65 years of age, and the prevalence exceeds 80% among those ≥75 years of age.1,2  Moreover, half of adults 75 years of age or older have four or more chronic conditions, and over 20% have six or more coexisting illnesses.1

References

Question 2:
Define polypharmacy.

Answer: Treatment guidelines for individual diseases recommend the use of drugs for that disease.  However, if all of the relevant treatment guidelines are followed for an older individual with multiple concurrent diseases, the resulting large number of prescribed drugs represents polypharmacy.  Thus, the use of multiple concomitant medications is a natural consequence of the multiple co-morbid conditions that increase in prevalence with aging and is especially common among patients aged 85 years and older.  Polypharmacy is generally defined as concurrent prescription of 5 or more medications.1  In a longitudinal analysis of prescribing for individuals aged 62-85 years of age in the US, the prevalence of polypharmacy was 36% in 2010-2011.2  As discussed,  the number of concurrent medications is a strong predictor of and risk factor for adverse drug effects.  Managing polypharmacy is a significant challenge in geriatric medicine.

References

  • Gnjidic D, Hilmer SN, Blyth FM, et al. Polypharmacy cutoff and outcomes: five or more medicines were used to identify community-dwelling older men at risk of different adverse outcomes. J Clin Epidemiol 2012;65:989-995.
  • Quato DM, Wilder J, Schumm LP, et al. Changes in the prescription and over-the-counter medication and dietary supplement use among older adults in the United States, 2005 vs 2011. JAMA Intern Med 2016;176:473-482.
  • Steinman MA, Miao Y, Boscardin WJ, Komaiko KDR, Schwartz JB. Prescribing quality in older veterans: A multifocal approach. J Gen Int Med 2014:29 1379-1386.

Question 3:
Aging in humans is associated with which of the following changes in cardiovascular function?

A. Decreased blood pressure
B. Increased pulse pressure
C. Decreased total peripheral resistance
D. Increased pulse wave velocity

Answer: B, D
Cardiovascular aging in humans is associated with increased pulse pressure and increased pulse wave velocity.  Increases in calcium and collagen in the arterial and ventricular walls result in increased arterial stiffness throughout the cardiovascular system.  The hemodynamic consequences include elevated central aortic pressures, increased pulse wave velocity, and widened pulse pressure (the difference between systolic and diastolic blood pressure).  The shape of the aortic pulse wave is altered due to the reduced elasticity and compliance and there is earlier reflection back of the arterial pulse wave.  The increased stiffness of the ventricles results in less complicance and impaired relaxation rates that reduce diastolic filling and filling rates.  Nonetheless, cardiac output at rest is usually preserved.

References

  • Laurent S, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 2006; 27:2588-2605.
  • O’Rourke, MF, Hashimoto J. Mechanical factors in arterial aging: a clinical perspective. J Am Col Cardiol 2007; 50:1-13.
  • Lakatta EG, Want M, Najjar SS. Arterial aging and subclinical arterial disease are fundamentally intertwined at macroscopic and molecular levels. Med Clin North Am 2009; 93:3;583-604.

Question 4:
Which of the following responses are decreased in older patients?

A. Sedation
B. Beta adrenergic blockade
C. Beta adrenergic stimulation
D. Muscarinic cholinergic inhibition

Answer: B, C
In older patients, beta adrenergic blockade and beta adrenergic stimulation are both impaired. Beta adrenergic responses are impaired as an increasing function of age—both chronotropic and inotropic responses.  The most consistently observed and clinically relevant age-related change is the decreased heart rate response to exogenous beta-adrenergic stimulation (the amount of isoproterenol, a Beta 1 agonist required to increase heart rate, goes up dramatically with age: example shown of Vestal, Clin Pharm Ther 2:181-6 1979) or endogenous beta-adrenergic stimulation during exercise, stress, infection, or volume loss.  This is illustrated in the commonly used formula to estimate maximal heart rate: 220-age (in years) for men and 226-age for women.  Baroreflex responses that involve parasympathethic activation as well as beta-adrenergic sympathetic stimulation during standing or volume loss are also blunted, leading to increased risk of postural hypotension.

References

Vestal RE, Wood AJ, Shand DG, Reduced beta-adrenoreceptor sensitvity in the elderly. Clin Pharm Ther 1979 Aug; 26(2):181-6.

Craft N, Schwartz, JB. Effects of age on intrinsic heart rate, heart rate variability, and AV conduction in healthy humans. Am J Physiol 1995;268: H1441-1452.

Question 5:
Which of the following is the most marked and consistent change in drug clearance and elimination with aging?

A. Decreased phase 1 CYP3A mediated drug metabolism
B. Decreased renal drug elimination
C. Increased phase 2 drug glucuronidation
D. Increased drug acetylation

Answer: B
Changes in renal function represent an important and probably the most consistent PK change with aging.  Renal clearance by all routes – glomerular filtration, renal tubular secretion or renal tubular reabsorption – decrease with age (about 10% per decade) and are lower in women than men at all ages.  There are two principal pathways for drug excretion by the kidney: glomerular filtration and tubular secretion.  Glomerular filtration plays a major role with non-protein-bound small molecules (i.e., of a size that can pass through the glomerular capillary wall).  Examples of drugs commonly used in older individuals that are eliminated by renal clearance are aminoglycoside antibiotics, direct acting oral anticoagulants, and furosemide and chemotherapeutic agents such as cisplatin, carboplatin, hydroxyurea, methotrexaste, and oxaliplatin.

For drugs in which renal excretion is an important determinant of elimination of the intact drug or an active metabolite, dose adjustment is often required if renal function is impaired.  Dose adjustment is based on estimation of GFR.  There is some debate as to the best estimate method for GFR.  Many clinical laboratories routinely report an estimated GFR by either the non-linear Modification of Diet in Renal Disease [MDRD] or Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] methods that include age, serum creatinine, and sex, as well as black race as a factor, but do not include weight.  These two methods may be more accurate at higher eGFR but generally provide higher estimates of renal clearance in the elderly compared to the Cockcroft-Gault method that is based on age, serum creatinine, weight, and sex.  Dosage adjustments should be based on the evidence-based methods indicated in FDA-approved package inserts.  For most currently available renally-cleared drugs, this is by estimating creatinine clearance using the Cockcroft-Gault method.

References

Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41.

Levey AS, Greene T, Kusek JW, et. al. A simplified equation to predict glomerular filtration rate from serum creatinine. J Am Soc Nephrol 11:A0828, 2000.

Levey A, Stevens L, Schmid C, Castro Ar, Feldman H, Kusek J, et al. CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604-12.

Ix J, Wassel C, Stevens L, Beck G, Froissart M, Navis G, et al. Equations to estimate creatinine excretion rate: the CKD epidemiology collaboration. Clin J Am Soc Nephrol 2011;6(1):184-91.

Additional Note: Drug Metabolism

Pharmacokinetic changes due to aging are mostly seen in Phase 1 enzymes, which oxidatively metabolize drugs.  Some Phase 1 drugs commonly used in older individuals are biotransformed by Cytochrome P450 (CYP) enzymes.  For example, amlodipine, atorvastatin, clarithromycin, diltiazem, fentanyl, lovastatin, midazolam, nifedipine, and verapamil are biotransformed by CYP3A.  Investigations of age-related changes in metabolism of CYP3A agents have found age-related effects to be of far less magnitude than those of renal clearance and to be highly variable in clinical populations.  While i.v. bolus studies in men have shown age-related decreases in CYP3A clearance, these changes may be absent in older women or men during chronic oral therapy of CYP3A-metabolized medications.  Thus, dosage adjustment of chronically administered medications cleared by CYP enzymes is not routine – unless based on increased sensitivity to the drug effects such as seen with CNS depressants or those with anticholinergic effects.

References

Abernethy DR, Schwartz JB, Todd El, et al. Verapamil pharmacodynamics and disposition in young and elderly hypertensive patients. Ann Intern Med 1986;105:339-336.

Cotreau MM, von Molte LL, Greenblatt DJ. The influence of age and sex on the clearance of cytochrome P4503A substrates. Clin Pharmacokinet 2005;44:33-60.

Schwartz JB, Abernethy DR. Aging and medications: Past, Present, Future. Clin Pharmacol Ther 2009:85:3-10.

Verotta D, Schwartz JB. Population analyses of atorvastatin inpatients living in the community and nursing homes. Clin Pharm Ther 2009:86:497-502.

Question 6:
A 72-year-old woman weighs 105 pounds (48 kg) and has serum creatinine of 0.9 mg/dL.  What is the estimated renal glomerular filtration rate calculated using the Cockcroft Gault equation?

Answer:
Formula for the Cockroft Gault equation:

Creatinine clearance (mL/min)

= (140-age) (weight in kg)/72 (serum Cr in mg/dL) (times 0.85 if a woman)

Result:

CrCl = (140-72) (48 kg)/72 (0.9 mg/dL) = 50.4 mL/min for males

For females, reduce by 15%:

CrCl for this patient = 0.85 x 50.4 = 42.8 mL/min

Calculation using two additional methods:

Using the MDRD equation for eGFR and assuming she is white:

eGFR = 61.6 mL/min/1.73 M2

if a man = 83 mL/min/1.73 M2

Using the CKD-EPI equation for eGFR and assuming she is white:

eGFR = 69 mL/min/1.73 M2

if a man = 85 mL/min/1.73 M2

Dosing recommendations in FDA-approved postmarketing labels are often based on creatinine clearance based on the Cockcroft and Gault equation1 that incorporates age, weight (measured and not ideal), serum creatinine, and a sex factor, while laboratories routinely report estimated glomerular filtration rate (eGFR) that can provide higher estimates of renal clearance and estimated doses of direct oral anticoagulants (DOAC) in older and smaller individuals.  The Cockcroft and Gault equation was developed from a limited population sample with non-standardized creatinine measurements.  Subsequent research has led to the development of a series of formulae by the Modification of Diet in Renal Disease Study [MDRD] and Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] that more closely estimates glomerular filtration rates at higher rates and defines renal disease status2-4.  Clinical laboratories now use standardized creatinine measurements and routinely report GFR with either the MDRD or the CKD-EPI equations that incorporate age, sex, serum creatinine, and race, and do not include weight.  Results are reported as mL/min/1.73 M2.  Laboratories do not currently report creatinine clearance as estimated by the Cockcroft and Gault equation or body surface area-corrected estimates of eGFR.  As demonstrated in the calculations above, estimates of renal clearance vary based on the equation used5, and it is recommended that the calculations be done with the equation used in the clinical trials that have led to drug approval, as this may vary.

References

  • Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41.
  • Levey A, Bosch J, Lewis J, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999;130(6):461-70.
  • Levey A, Stevens L, Schmid C, Castro Ar, Feldman H, Kusek J, et al. CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604-12.
  • Ix J, Wassel C, Stevens L, Beck G, Froissart M, Navis G, et al. Equations to estimate creatinine excretion rate: the CKD epidemiology collaboration. Clin J Am Soc Nephrol 2011;6(1):184-91.
  • Schwartz, JB. Potential impact of substituting estimated Glomerular Filtration Rate for estimated Creatinine Clearance for dosing of Direct Oral Anticoagulants. J Am Geriatr Soc 2016 1996-2002.

Question 7:
Describe changes in body composition that occur in older as compared to younger individuals.

Answer:
On average, body size decreases with aging and body composition changes, resulting in higher body fat and less muscle mass than in younger individuals.  Intravascular volume and total body water also decrease.  The clinical implications are that initial loading doses of medications may need to be adjusted for body size or intravascular volumes.  For chronic medication therapy, fat-soluble medications will have a larger volume of distribution and may accumulate in fat.

References

Lesser GT, Markofsky J. Body water compartments with human aging using fat-free mass as the reference standard. Am J Physiol 1979 Mar;236(3):R215-20.

Chumlea WC, Roche AF, Webb P. Body size, subcutaneous fatness and total body fat in older adults. Int J Obes 1984;8(4):311-7.

Borkan GA, Hults DE, Gerzof SG, Robbins AH. Comparison of body composition in middle-aged and elderly males using computed tomography. Am J Phys Anthropol 1985 Mar; 66(3):289-95.

Schwartz RS, Shuman WP, Larson V, et al. The effect of intensive endurance exercise training on body fat distribution in young and older men. Metabolism 1991:40(5):545-51.

Question 8:
Which of the following drug effects can impair functional status in older individuals?

A. Blood pressure lowering
B. Sedation
C. Gastric acid inhibition
D. Anticholinergic

Answer: A, B, D

Older age is associated with increased effects of several drug classes and may be most frequent for medications with sedative hypnotic and anticholinergic effects.  Adverse effects are most likely to be observed in systems with the least reserve. For example, with decreasing cognition, sedative hypnotic and anticholinergic effects tolerated in younger individuals may lead to confusion or delirium in older individuals and may also lead to falls.  Sedation and anticholinergic drug response are common off-target effects of drugs and can impair functional status in older individuals.  Similary, orthostatic hypotension may occur in the older individual with decreased baroreflex responses who is receiving vasodilating, beta- or alpha-blocking, or potent antihypertensive medications, and could result in falls or fractures.

References

Hilmer SN, Gnjidic D, Abernethy DR. Drug Burden Index for international assessment of the functional burden of medications in older people. J Am Geriatr Soc 2014;62(4):791-2.

Tinetti ME, Han L, Lee DS, et al. Antihypertensive medications and serious fall injuries in a nationally representative sample of older adults. JAMA Intern Med 2014 Apr;174(4):588-95.

Jamieson HA, Nishtala PS, Scrase R, et al. Drug Burden and its Association with Falls Among Older Adults in New Zealand: A National Population Cross-Sectional Study. Drugs Aging 2017 Dec 8. doi: 10.1007/s40266-017-0511-5. [Epub ahead of print]

Presented by the PhRMA Foundation Safe and Effective Prescribing Project

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