Pharmacodynamics of Aging

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

Question 2:
Define polypharmacy.

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

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

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

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?

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

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

Case Study 1
A 78-year-old woman presents to the emergency room after a fall in her home.  She is in considerable pain, and on examination she has a left hip fracture.  She is alert and oriented, and says that as she was getting out of bed she became dizzy, tripped on a rug, and fell to the floor.  Her past medical history is positive for myocardial infarction 5 years ago, osteoarthritis, type 2 diabetes mellitus, and depression.  Her husband of 52 years died 4 years ago and she has lived alone in their home since that time.  She has no medication allergies, does not drink alcohol and has never smoked.  She says that she walks most days, usually for a half hour, and prior to the fall was feeling well.  Current medications are low dose aspirin (75 mg/day), metoprolol, naproxen, pantoprazole, metformin, and citalopram.

On physical examination she is a thin (5’4”, 102 lbs, BMI 18) woman in moderate distress.  Blood pressure is 164/75 mm Hg, heart rate 84/minute and regular, temperature 97 ˚F, and respirations 18/minute.  She has pain with movement of the left leg, otherwise the examination is unremarkable.  She is taken to the operating room for surgical repair of the hip, and returns from the operating room receiving low molecular weight heparin.

1. Discuss the age-related differences in response to this patient’s medications prior to the hip fracture.
2. Discuss the approach for reinstitution of the patient’s medications following the surgery.
3. Discuss polypharmacy as it relates to the patient.
4. Discuss medications that should be avoided in the patient during her post-operative and convalescent period.

Case Study 2
An 84-year-old man with congestive heart failure, chronic obstructive pulmonary disease, osteoarthritis, and benign prostatic hypertrophy has increasing shortness of breath.  His physical examination is consistent with congestive heart failure that has recently worsened.  He lives in an assisted living facility and has limited mobility, though is able to walk to the bathroom and dining room.  Current medications are lisinopril, carvedilol, furosemide, low dose aspirin, albuterol, ibuprofen, terazosin and oxybutynin.

1. Discuss the age-related differences in response to medications that this patient is receiving.
2. Discuss the mechanism of orthostatic hypotension that the patient may experience associated with the terazosin therapy.
3. Discuss the effects of oxybutynin in the patient and why it may not be an optimal therapy.

Case Study 1 (See Table 1, below)

1. Discuss age-related differences in response to this patient’s medications prior to the hip fracture.

Prior to the hip fracture, the patient is taking low dose aspirin, metoprolol, naproxen, pantoprazole, metformin, and citalopram.

Because of the patient’s age, a reduction in renal function is likely.  The patient’s renal function should be evaluated because the co-administration of an NSAID (naproxen) with a beta blocker (metoprolol) could decrease renal function.  The co-administration of aspirin with an NSAID increases the risk of GI bleeding, and this risk is even greater in older patients than in younger patients receiving these combined medications.  The addition of citalopram might further increase this risk.  There are limited data on age-related differences in responses to hypoglycemic agents; however, symptoms of hypoglycemia may not be recognized by older patients or may present as confusion and/or cognitive changes, and beta-adrenergic responses will be blunted by age-related changes and further impaired by the co-administration of the beta blocker metoprolol.

2. Discuss the approach for reinstitution of this patient’s medications following the surgery.

After surgery, medications that increase the risk of bleeding should be avoided while the patient is receiving LMW heparin.  Specifically, the aspirin and naproxen should not be co-administered.  The potential bleeding enhancing effects of citalopram are of smaller magnitude and, because the patient will be anticoagulated for at least a month after total hip replacement and because the antidepressant effects of citalopram may take weeks to achieve therapeutic effects, this drug could likely be reinstituted when the patient begins food intake.

Because the use of pantoprazole increases the risk of C. difficile in hospitalized patients, its reinstitution should also be delayed or it should be considered for discontinuation in the absence of prior ulcer disease or bleeding complications with her medication regimen or prior anticoagulation.

Metoprolol should be resumed as soon as possible after surgery in patients with cardiovascular disease as sensitivity to adrenergic stimulation can occur after discontinuation and result in increases in cardiac events, especially during times of increased stress such as the postoperative state and rehabilitation.  Blood pressure should be evaluated in the standing position as well as when supine to avoid postural hypotension and falls.  Low-dose aspirin can usually be resumed shortly after surgery if there are no bleeding complications but can be delayed for several days.  Naproxen should be withheld until after anticoagulation has been discontinued, and other pain medications can be used if needed.  Acutely, this may require opiates, in which case a bowel regimen should accompany opiate use, as should careful monitoring for unwanted opiate effects.  For chronic pain, acetaminophen is considered first-line for older patients although many will not have adequate pain relief and may require additional medications.  There is no ideal second-line medication as NSAIDs increase bleeding risk and may confer a slightly higher cardiovascular risk in patients with CVD, yet may provide significant relief of chronic pain while opiates have many unwanted CNS and bowel effects.

3. Discuss the potential consequences of polypharmacy as it relates to this patient.

Prior to admission, she was receiving six daily medications, a number that meets all definitions of polypharmacy and increases her risk of unwanted medication interactions.  Specific potential drug-drug interactions include:

1) Co-administration of an NSAID (Naproxen) and a salicylate (Aspirin) increase the risk of GI toxicity.

2) Citalopram further increases this risk, as does LMW heparin.

3) Co-administration of a beta blocker (metoprolol) with an NSAID (Naproxen) may reduce the antihypertensive effect of the beta blocker.

4) Co-administration with citalopram may increase the plasma levels of the beta blocker.

5) It is likely that the pantoprazole was thus prescribed to reduce the risk of bleeding created by these multiple medications—and is an example of the prescribing cascade where medications are prescribed to counter the adverse effects of other prescribed medications, further increasing the number of medications.

4. Discuss medications that should be avoided in this patient during her post-operative and convalescent period.

After surgery, the patient should avoid medications with anticholinergic or sedative effects as the CNS threshold for delirium is both lower in older patients and further lowered with these medications.  Urinary retention is also a potential unwanted effect that may occur with anticholinergic medications—but most commonly in older men.

Table 1: Drug Summary for Case 1

Drug	Reason for use	Mechanism	Metabolism	Interactions with co-administered drugs	Age-related changes in dosing/monitoring
Aspirin  (Low dose)	Secondary prevention of cardiovascular disease	Inhibition of COX-1 (and COX-2)		NSAIDs,salicylates, (and after surgery anticoagulants) increase risk of GI bleeding	Monitor for bleeding/bruising    Monitor renal function
Metoprolol	Treatment of angina and hypertension and secondary prevention of recurrent MI	Beta-adrenergic blockade	Primarily CYP2D6	Co-administration with NSAIDs may worsen renal function    NSAIDs may diminish anti-hypertensive effects   May increase risk of hypoglycemia with exercise and oral antidiabetic agents	Monitor renal function      Monitor blood pressure     Monitor glucose
Naproxen	Anti-inflammatory-arthritis	Inhibition of COX-1 and COX-2  Inhibition of prostaglandin synthesis	Metabolized in liver	Increases GI bleeding risk with anticoagulant or antiplatelet agents (aspirin, heparin) and SSRIs  May decrease cardioprotective effect of aspirin   May decrease antihypertensive effects of beta blockers	Use lowest effective dose for shortest time possible          Monitor blood pressure   Avoid in patients with moderate renal impairment
Pantoprazole	Gastroprotection  from aspirin and naproxen	Proton Pump Inhibition- suppresses gastric acid secretion	Main pathway is CYP2C19  Minor pathway is CYP3A4, 2D6, and 2C9	Increases risk of C. difficile in hospitalized patients  Increases risk of bone loss and fracture in outpatients High binding to serum protein OK to administer with metoprolol	Use for shortest time possible    No dosage adjustments recommended
Citalopram	Antidepressant	Selective serotonin reuptake inhibition (SSRI)	Primary enzymes involved in metabolism are CYP3A4 and CYP2C19	Potential increased risk of upper GI bleeding with aspirin, NSAIDs, and LMW heparin    May enhance the hypoglycemic effect of blood glucose lowering agents	Decreased clearance  Increased half-life in elderly -> Reduced maximum daily dose -20 mg/day vs 40 mg/day in younger individuals
Low Molecular Weight Heparin	Anticoagulant		Metabolized in liver by desulfation or depolymeriza-tion	Aspirin and NSAIDs may increase bleeding, and the bleeding risk is increased further with heparins	Increased exposure with renal impairment-adjust dosages    May have difficulty with injections/cost

Reference: Drugs.com, Lexicomp, RxList

Case Study 2 (See Table 2, below)

1. Discuss the age-related differences in clearance and responses to medications that this patient is receiving.

The patient is recceiving lisinopril, carvedilol, furosemide, low dose aspirin, albuterol, ibuprofen, terazosin, and oxybutynin.

Because of the patient’s age, a reduction in renal function is likely, and this reduction could affect his clearance of lisinopril and furosemide.  In addition, about 20-30% reduction in clearance of drugs metabolized by CYP3A4 in older men has been reported variably, and this reduction could affect the clearance of oxybutynin.

Albuterol is a beta-2 adrenergic agonist.  With older age, beta adrenergic responses of bronchodilation are blunted, and the amount of drug required could increase.  An increase in adverse cardiovascular effects including atrial arrhythmias or increased myocardial demand leading to ischemia is also possible.

Carvedilol is a non-selective beta blocker with alpha-blocking activity.  Due to age-related decreases in beta-adrenergic autonomic nervous system responses, beta-adrenergic blockade may result in less hemodynamic response than seen in younger adults.  However, no age-related changes in dosages are recommended for the treatment of heart failure.  Alpha-blocking activity may be conserved with aging, leading to the possibility of greater hypotensive effects, especially with standing.  In U.S. trials conducted by the manufacturer, hypertensive elderly patients had a higher incidence of dizziness than younger patients.  Carvedilol should be administered with food to minimize the risk of orthostatic hypotension.

Terazosin is an alpha-1 adrenergic blocker.  It may enhance the antihypertensive effects of other alpha-1 blockers.  With older age, the magnitude of reflex heart rate response is also blunted.  This can cause marked lowering of blood pressure and orthostatic hypotension.

Ibuprofen increases the risk of G.I. bleeding in the elderly with a less frequent potential for increasing cardiovascular events in patients with coronary artery disease.

Oxybutynin has anticholinergic effects and can cause confusion and blurred vision, which can decrease the functional capacity in the elderly and increase the drug burden index.  It can also cause constipation, tachycardia, or urinary retention in the presence of benign prostatic hyperplasia (BPH).  It should be avoided in the presence of delirium or dementia.

2. Discuss the mechanism of orthostatic hypotension that this patient may experience associated with the terazosin therapy.

Orthostatic hypotension (OH) is a drop in blood pressure that occurs upon standing. Orthostatic hypotension is associated with higher risk of falls, coronary heart disease, stroke, and death.

Physiologic responses to standing occur to avoid pooling of blood in the venous system due to gravity and prevent decreased cardiac output.  These responses include:

• Local sensing of perfusion/pressure decreases in the arterial walls (especially carotids) and endothelial responses of vasoconstriction
• Baroreceptor—senses fall in central pressure and sends signal for parasympathetic withdrawal at the sinus node resulting in increases in heart rate (first 30 or so seconds) followed by beta-adrenergic stimulation that produces norepinephrine release and increases in heart rate and triggers vasoconstriction by multiple mechanisms in the periphery
• Renal-endocrine—senses perfusion/pressure leading to renin angiotensin system activation; AT1—vasoconstriction, antidiuresis (through chemoreceptors)

Arterial changes associated with aging include reduced elasticity and compliance, increased pulse pressure, and decreased endothelial and baroreceptor sensitivity.  The blunted reflex responses of the baroreceptor also include decreased sensing of pressure changes in addition to the diminished beta-adrenergic (chronotropic and inotropic) and parasympathetic responses to autonomic stimulation at every level.  These changes, combined with the vasodilating or alpha-contriction blocking effect of terazosin, markedly increase the risk of postural hypotension.  Of lesser impact are age-related decreases of the renin-aldosterone system to respond to decreased perfusion (upon standing).  His medications that could lead to orthostatic hypotension include the following, in order of importance:

• Terazosin alpha blocker prevents constriction
• Carvedilol is also further blocking heart rate responses and providing additional alpha-blockade
• Lisinopril lowers blood pressure and further blocks renin-angiotensin responses

3. Discuss the effects of oxybutynin in this patient and why it may not be an optimal therapy.

Oxybutynin has anticholinergic effects and can cause confusion and blurred vision, which can decrease the functional capacity in the elderly and increase the drug burden index.  It can also cause constipation, tachycardia or urinary retention in the presence of benign prostatic hyperplasia (BPH).  It should be avoided in the presence of delirium or dementia.

Table 2: Drug Summary for Case 2

Drug	Reason for use	Mechanism	Metabolism	Interactions with co-administered drugs	Age-related changes in dosing/monitoring
Lisinopril	Treatment of high blood pressure and congestive heart failure	Angiotensin converting enzyme (ACE) inhibitor	Excreted unchanged in the urine	May cause excessive reduction in BP with diuretics (additive effects with thiazide diuretics)  Antihypertensive effects may be attenuated by NSAIDs Coadministration with NSAIDs may result in decrease in renal function	Potentially greater hypotensive effects/postural hypotension  Monitor renal function
Carvedilol	Treatment of heart failure and hypertension	Beta blocker with alpha blocking activity	Primarily by CYP2D6 and 2C9.  Less by CYP3A4, 2C19, 1A2, and 2E1	Take with food to minimize orthostatic hypotension	Higher incidence of dizziness in older patients
Furosemide	Loop diuretic to treat fluid retention in congestive heart failure	Inhibits absorption of sodium and chloride in the kidney	Excreted unchanged in the urine	NSAIDs can decrease response to furosemide  May cause hypotension and decrease in renal function with ACE inhibitors	Renal clearance is lower in the elderly, who are more likely to have decreased renal function  Monitor renal clearance
Aspirin  (Low dose)	Reduction of cardiovascular risk	Inhibition of COX-1 (and COX-2)		NSAIDs and salicylates increase risk of GI toxicity	Monitor renal function
Albuterol	Treat or prevent bronchospasm	Bronchodilator, Beta-2 adrenergic agonist, relaxes muscles in airways	Primarily by sulfotransferase SULTIA3	Beta blockers should be administered with caution  Hypokalemia from loop diuretics can be worsened	Increased risk of atrial arrhythmias events from beta adrenergic stimulation
Ibuprofen	Anti-inflammatory  (NSAID)	Inhibition of COX-1 and COX-2Inhibition of prostaglandin synthesis		Can decrease response to loop diuretics (furosemide)  May reduce anti-hypertensive effect of ACE inhibitors May worsen renal insufficiency associated with jACE (Lisinopril)	Higher risk of bleeding  Slightly increases risk of CV events in patients with CVD Use for shortest duration possible
Terazosin	Improve urination in men with BPH	Alpha-1 adrenergic blocker	Highly bound to plasma proteins  Minimal hepatic first-pass metabolism	Additive alpha blockade with carvedilol	Causes lowering of BP  Can cause orthostatic hypotension
Oxybutynin	Treat symptoms of overactive bladder	Antispasmodic effect on smooth muscle and inhibits muscarinic action of acetylcholine on smooth muscle	Mainly CYP3A4	Anticholinergic effects may decrease GI motility and reduce absorption of other drugs	Anticholinergic effects can decrease functional capacity and increase the drug burden index  Decreased clearance of drugs metabolized by CYP3A

Reference: Drugs.com, Lexicomp, RxList

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

• U.S. Department of Health and Human Services. HHS Initiative on Multiple Chronic Conditions. 2014. Available at: http://www.hhs.gov/ash/initiatives/mcc/
  Accessed 08-Jan-2018.
• U.S. Department of Health and Human Services. Multiple Chronic Conditions – A Strategic Framework: Optimum Health and Quality of Life for Individuals with Multiple Chronic Conditions. Available at: http://www.hhs.gov/sites/default/files/ash/initiatives/mcc/mcc_framework.pdf
  Accessed 08-Jan-2018.

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 status^2-4.  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]