Appropriate prescribing

6


Appropriate prescribing





Objectives


Upon completion of this chapter, the reader will be able to:


• Describe physiologic changes that may impact how medications should be used in older patients.


• Outline a prescribing strategy to maximize benefit and minimize harm.


• Explain how prescription drug coverage impacts use of medication in geriatric patients.


• Explain how pharmacists add value to the geriatric health care team.


The older population is prescribed more medications than any other age group.1 With initiation of Medicare Part D in 2006, all 43 million Medicare beneficiaries had immediate access to outpatient prescription drug plans. By June 2006, 90% of beneficiaries were enrolled in Medicare D or a creditable drug coverage plan.2 The Agency for Healthcare Research and Quality (AHRQ) reports that older people fill 31.6 prescriptions annually,1 as well as having more unique prescriptions and more refills than the younger population. In 2009, the New England Healthcare Institute addressed the issue of medication nonadherence for chronic diseases. Chronic diseases account for 75% of health care spending in the United States, and the cost of medication nonadherence reached $100 billion in terms of excess hospital admissions alone.3


Over the past two decades, the cost of prescriptions has increased more rapidly than increases in the gross domestic product. In 2009, it was estimated that total expenditures for prescriptions in noninstitutionalized patients over 65 years was $86.5 billion in the United States.4 This figure does not include any over-the-counter medications or medications given in a physician’s office, in a clinic, or in the inpatient setting.



CASE 1   LM (Part 1)


LM is a 76-year-old female with a past medical history of atrial fibrillation, systolic heart failure, hyperlipidemia, and migraines. She visits you, her primary care physician, complaining of intermittent palpitations. She denies chest pain, shortness of breath, pain, unusual bleeding, swollen extremities, weight gain, or headache. Her chronic medications include warfarin 3 mg daily, metoprolol tartrate 100 mg twice daily, digoxin 0.125 mg daily, lisinopril 20 mg daily, and simvastatin 40 mg daily. She is also taking amitriptyline 150 mg at bedtime for migraine prophylaxis. Her vital signs reveal a blood pressure of 120/75 mmHg, which is near baseline, and an irregularly irregular heart rate of 130 to 150. You perform an electrocardiogram that reveals atrial fibrillation with a rapid ventricular rate. A recent serum digoxin concentration was reported to be 0.9 mcg/L (upper limit considering atrial fibrillation with concomitant systolic heart failure). You decide to initiate LM on amiodarone as her metoprolol and digoxin are at the maximum recommended doses.





Pharmacokinetic changes in the elderly


Clinical pharmacokinetics is the discipline describing drug behavior with regard to absorption, distribution, metabolism, and elimination with the intent to use medications effectively while limiting adverse effects. Aging brings physiologic changes that affect these four characteristics in a clinically meaningful and relevant way. With age, organ function and physiologic reserve both decline, resulting in enhanced susceptibility to adverse effects of medications.5–7 See Table 6-1.




Absorption


Medications (except those given parenterally) are subject to variations in absorption. Bioavailability of oral medications may fluctuate with changes that are common in older patients such as reduced acidity of the stomach, gastric motility, and first-pass metabolism. Medications that require an acidic environment for optimal absorption (e.g., calcium carbonate or ketoconazole) have reduced absorption in patients with hypochlorhydria (whether physiologic or acid suppressant–induced). Fortunately, most medications do not require active transport to be absorbed and passive diffusion remains relatively unchanged in most older patients. Absorption of topical medications (e.g., creams, ointments, or patches) may fluctuate because of changes in the skin such as atrophy and reduced blood flow to the dermal layer. Although some medications may have reduced absorption, this is frequently counterbalanced by a decreased first-pass effect. For medications that have a low bioavailability in average adults, such as propranolol or morphine, a small decrease in the initial first-pass effect may drastically impact drug serum concentrations. Although absorption may be the pharmacokinetic factor least impacted by age, alterations in absorption should be considered when the patient response varies from what is expected.



Distribution


A medication’s distribution describes the extent to which a drug passes into different body compartments. Depending on drug characteristics such as size, solubility, and plasma-binding affinity, a medication may be more likely to achieve higher concentrations in hydrophilic or lipophilic compartments or to pass through the blood-brain barrier. Older patients have lower total body water and higher body fat. Therefore lipophilic medications have a larger volume of distribution. This leads to a longer elimination phase and prolonged therapeutic or toxic effect because drugs are typically not efficiently eliminated from the lipid compartment. Examples of lipophilic medications include phenytoin, valproic acid, diazepam, olanzapine, amiodarone, and lidocaine.


Medications reach equilibrium between compartments and also between bound and free forms. As patients age, albumin and alpha-1-acid glycoprotein may decrease or increase, resulting in higher or lower free fractions of medication. Alterations to concentrations of these proteins are not caused by aging but rather by chronic conditions. For example, serum albumin decreases with prolonged illness, raising the free fraction of highly bound acidic drugs such as naproxen, phenytoin, and warfarin. With illness, patients may develop adverse events or side effects from a medication that was previously well tolerated. This is particularly true for medications needing a closely maintained therapeutic range, such as warfarin and phenytoin. Serum drug concentrations of the total (bound and free fractions) should be monitored because the free fraction may be in a toxic range, while the bound level is therapeutic.



Metabolism


Metabolism is the body’s process of altering a medication in some way. In the liver, the result of metabolism may be a product that is more or less active in the body or one more easily eliminated by the kidneys or biliary tree. Aging decreases liver size and blood perfusion, but quantitative changes in liver function and histology are minimal. Metabolism of medications usually occurs via reactions that are classified into one of two phases. Phase I metabolism occurs via cytochrome P450 isoenzymes, which have a high interpatient variability even in young adults. Studies of changes in specific isoenzymes with age are plagued by small sample sizes, confounders such as effects of smoking and genetic polymorphism, and the potential to interpret cohort effects as age-related effects. However, studies suggest a decrease in elimination of substrates of 1A2 and 2C19, a decrease or no change in elimination of substrates of 3A4 and 2C9, and no change in elimination of substrates of 2D6.5,7 These phase I reactions result in an oxidized, reduced, or hydrolyzed form of the parent drug but not all medications must pass through this step. Interindividual variability and confounders (listed earlier) affect phase I metabolism more than aging does. However, attention must be paid to medications with a high hepatic extraction ratio such as lidocaine, morphine, labetalol, propranolol, verapamil, and imipramine.


Many medications, such as lorazepam and oxazepam, are metabolized only through the phase II reactions glucoronidation, acetylation, or sulfation, resulting in larger, more water soluble, more easily eliminated metabolites. Evidence thus far suggests that phase II is unaffected by aging.



Elimination


Elimination of medications generally occurs via conversion to inactive metabolites in the liver, excretion in bile, or elimination through the kidneys. The rate at which medications are excreted in the urine is determined by a combination of glomerular filtration, tubular secretion, and reabsorption. With age most patients experience a decline in glomerular filtration rate. Nomograms and algorithms have been developed and validated to estimate glomerular filtration by calculating the estimated creatinine clearance. Creatinine is cleared by glomerular filtration and active tubular secretion. These equations were typically determined using healthy adults. With this in mind, validity of these equations in patients at extremes of age and with active disease is less reliable. Given these limitations, the Cockcroft-Gault equation is the recommended equation for most scenarios. Other equations, such as the modification of diet in renal disease (MDRD) equation, may automatically calculate the estimated glomerular filtration rate in some electronic medical records and results may vary substantially from those of the Cockcroft-Gault equation. As with any patient encounter, the entire scenario needs to be considered in addition to the calculated creatinine clearance (CrCl). The Cockcroft-Gault equation uses the following formula to determine CrCl:


Creatinine clearance (CrCl) mL/min = (140 − age) × weight/(72 × serum creatinine concentration), multiply by 0.85 for females



About two thirds of all older people experience a decline in creatinine clearance (CrCl). Despite limitations, estimated CrCl is a useful tool for estimating appropriate drug doses.



This equation uses serum creatinine concentration, which decreases in older patients because of their decreased muscle mass. This may result in a higher calculated CrCl, especially in underweight or malnourished older patients. To correct for these possibilities, many clinicians round the serum creatinine concentration up to 1 mg/dL, which may in turn underestimate CrCl. The estimated CrCl may vary drastically with extremes in weight. It has been suggested to use lean body weight when calculating CrCl in patients who are significantly obese. It is also important to appreciate that drug dosages and recommended dose adjustments for patients with renal impairment are based on estimated CrCl rather than on the often reported laboratory estimate of glomerular filtration, the MDRD.


It is important as a clinician to pay particular attention to dosages for medications that are eliminated unchanged in the urine or that have active metabolites that are eliminated in the urine because these drugs will accumulate in most older people.


Because of the variables discussed in this section, predicting a medication’s serum concentration or clinical effects may be difficult in a geriatric patient. The starting dose for most renally excreted drugs should be based on the estimated CrCl, but patients must be monitored for both overdosing and underdosing. For medications with a narrow therapeutic range or low ceiling for toxic effects, measuring serum drug concentrations is prudent, particularly when a patient is acutely ill.


In summary, the clinical impact of age-related changes in pharmacokinetics is difficult to predict. Vigilance to adverse effects of medications caused by altered drug pharmacokinetics is necessary in elderly patients and a thorough medication history is warranted in the presence of any new complaints. The adage to “start low and go slow” applies when initiating medications with potentially adverse effects.



In patients with significant renal impairment (creatinine clearance approaching 30 mL/min), refer to medication monographs for appropriate dosages for renally excreted drugs.




Pharmacodynamic changes in the elderly


Although numerous studies and reviews8–11 describe the pharmacokinetic changes in geriatric patients, there are limited data on age-related pharmacodynamic changes. Pharmacodynamics refers to the response of the body to a drug. Geriatric patients may have altered pharmacodynamics because of changes in receptor affinity or number, postreceptor alterations, and/or impairment of homeostatic mechanisms. Unfortunately, it is difficult to generalize age-related changes because studies have shown patients to have a higher “sensitivity” to some medications and a lower “sensitivity” to others. One example of higher sensitivity is increased central nervous system effects with benzodiazepines. One small study found that geriatric patients had a higher sensitivity index and a more profound central nervous system depressant effect, even when receiving a lower dose of midazolam.12 The opposite is found with beta-agonists/antagonists where patients tend to be less responsive to these agents. Some generalizations that can be made are that geriatric patients will frequently have a greater responsiveness to the central nervous system depressant effects of benzodiazepines, to the analgesic effects of opioids, and to the anticoagulant effects of warfarin and heparin.



CASE 1   LM (Part 2)

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Jun 8, 2016 | Posted by in GERIATRICS | Comments Off on Appropriate prescribing

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