Absorption

Physiologic changes of the GI tract with aging include increased gastric pH, delayed gastric emptying, reduced GI blood flow, and slowed intestinal transit. As a result of these changes, older persons can be expected to exhibit decreased bioavailability of medications with acid-dependent absorption, such as iron, and slowed absorption of medications, especially those that are enteric-coated.

Metabolism: First Pass

There is a 20% to 30% reduction in liver mass and hepatic blood flow with advancing age but perfusion of individual hepatocytes remains constant. Drug metabolism that depends on hepatic blood flow can be reduced in older persons. Changes in drug absorption with aging have been attributed to alterations in the metabolism of medications during their first pass through the liver, known as first pass metabolism. For example, morphine clearance is reduced about 33% in older persons leading to longer half-lives and the need for lower oral doses. The average clearance of propranolol declines, whereas the oral bioavailability increases. In the elderly there is a doubling of the bioavailability of chlormethiazole, lidocaine, labetalol, verapamil, propranolol, and levodopa. The practical consequences of alterations in drug absorption, bioavailability, and first pass metabolism result in the need to start with lower doses and perhaps longer dosing intervals between doses to avoid the risk of drug accumulation and toxicity.

Metabolism: Elimination

The effects of aging of the liver drug metabolizing enzymes are less clear. Activity of the cytochrome (CYP) P450 isoenzymes, 1A2, 2C9, 2C19, 2E1, and 3A4, may be decreased but do not universally result in reduced clearance of substrates for those enzymes. Variation in CYP function may be more related to changes in lifestyle and disease-related hepatic dysfunction than to aging. Drug metabolism by conjugation with glucuronic acid or oxidation is typically preserved with aging. As a result, studies of oxazepam, lorazepam, and temazepam have not identified changes in drug pharmacokinetics in older persons.

Renal Elimination

Renal function progressively declines with age independent of the development of any renal disease. By the age of 85 years the average creatinine clearance (ClCr) has declined to 50% of what it was at 25 years of age. The Baltimore Longitudinal Study of Aging prospectively found a decrease in ClCr of 0.75 mL/min/y. Most important is the potential to under recognize the decline in renal function when evaluating serum creatinine, soley. As a result of decreased production of creatinine with decreasing mobility and lower muscle mass in frail elderly individuals, serum creatinine can appear normal despite significant reductions in glomerular filtration rate (GFR) or ClCr. As a result, renal function should be estimated using either the modification in Diet for Renal Disease (MDRD) or Cockcroft and Gault equations for GFR or ClCr, respectively. Most clinical laboratories calculate GFR by MDRD whenever a serum creatinine is analyzed. Clinical pharmacists routinely use the Cockcroft and Gault equation to estimate ClCr for dosing of renal elimination of medications.

Older persons are subject to compromises in renal function secondary to progression of chronic conditions such as diabetes and hypertension. Hanlon and colleagues have published an extensive list of medications affected by renal impairment with recommendations for dosage reduction or avoidance. Among GI medications, ranitidine and cimetidine were recommended for dosage reduction in persons with ClCr less than 50 mL/min. The manufacturer recommends a 50% reduction in the dose of metoclopramide in patients with ClCr less than 40 mL/min.

Proton Pump Inhibitors

Proton pump inhibitors are generally considered safe and effective in older persons. Common adverse effects include headache, diarrhea, nausea, flatulence, and abdominal cramps. More serious consequences can occur with long-term administration of proton pump inhibitors. In a matched case-control study, patients older than 50 years of age who take proton pump inhibitors for more than 1 year were found to be at increased risk of hip fracture and the effect is dose-related. The investigators found that high-dose proton pump inhibitor therapy in long-term users increased the risk for hip fracture compared with nonusers (95% confidence interval [CI] 1.80–3.9, P <.001), perhaps as a result of reduced absorption of calcium. The lowest effective dose of proton pump inhibitors is recommended in older persons. Proton pump inhibitors have been associated with causing diarrhea induced by Clostridium difficile and should only be prescribed in individuals with a clear indication and for the shortest possible duration.

There is a clear relationship between drug exposure and the pharmacodynamic response (ie, gastric acid suppression, healing) to proton pump inhibitors. Proton pump inhibitors are absorbed well and should be taken approximately 1 hour before eating. Furthermore, because they are acid labile, proton pump inhibitors are manufactured as either enteric-coated granules within a capsule or enteric-coated tablets to inhibit degradation by gastric acid. Formulations should not be crushed or chewed before administration. A rapid-dissolving form of lansoprazole and a powdered form of omeprazole are available for nasogastric tube administration.

Proton pump inhibitors are extensively metabolized by the CYP 450 enzymes, primarily CYP3A4 and CYP2C19. CYP2C19 polymorphisms can significantly affect the metabolism of omeprazole and esomeprazole. Extensive metabolizers of omeprazole may require higher doses to achieve the same pharmacologic effect that poor metabolizers achieve on standard doses. Extensive metabolizers have been identified in 18% of the Swedish and Ethiopian populations but only 4% of the Chinese population. CYP2C19 activity has been shown to decline with age, such that even among extensive metabolizers, the metabolism of omeprazole is closer to that of poor metabolizers in much younger subjects. The net effect of the variances in CYP2C19 genotype and age are likely to result in the need for standard omeprazole dosing in most patients. Those extensive metabolizers with normal or intact CYP2C19 activity may be candidates for high-dose omeprazole but dosage should be governed by clinical response to therapy. The other proton pump inhibitors are metabolized to a much lesser extent or not at all by CYP2C19 and therefore are less likely to be affected by either the rapid CYP2C19 genotype or the decline in CYP2C19 function with age.

None of the proton pump inhibitors require dosage adjustment in patients with renal impairment, whereas the dosage of pantoprazole and rabeprazole should be decreased and these drugs should be used cautiously in patients with hepatic impairment.

Histamine-2 Receptor Antagonists

Important differences exist among histamine-2 antagonists that should be considered when selecting one of these agents in older persons. Cimetidine can cause thrombocytopenia, neutropenia, bradycardia, arrhythmias, confusion, depression, and gynecomastia. Cimetidine is associated with more clinically important drug interactions than the other histamine-2 antagonists because it inhibits CYP3A4 and CYP2C19 enzymes thereby decreasing the metabolism and increasing the effect of warfarin, phenytoin, theophylline, and some benzodiazepines. For these reasons and because of the larger frequency and severity of adverse reactions, cimetidine is not recommended in the elderly. Cimetidine and ranitidine have been reported to cause dyskinesia, whereas famotidine and cimetidine can cause impotence, particularly in high doses. Ranitidine has been found to have significant anticholinergic properties that may contribute to cognitive decline, constipation, dry eyes, and urinary retention in susceptible patients. Headache occurs in 4.7% and 3% of patients treated with famotidine and ranitidine, respectively. Ranitidine may inhibit CYP isozymes but famotidine and nizatidine are not metabolized by the CYP isoenzymes and do not have an inhibitory effect on hepatic clearance of other medications. All histamine-2 antagonists can cause reversible central nervous system side effects and thrombocytopenia.

All of the histamine-2 antagonists are cleared by glomerular filtration and dose reduction, by extending the dosing interval, is recommended even in persons with mild to moderate decreases in CrCl (ie, 30–60 mL/min). With severe renal impairment (CrCl <30 mL/min) the dosing interval should be extended further, the dose decreased, and patients observed for adverse central nervous system side effects.

Laxatives

All categories of laxatives can cause bloating, flatulence, and abdominal pain. Bulk-forming laxatives (eg, psyllium, methylcellulose, and polycarbophil) can cause constipation or impaction if they are not taken with sufficient fluids. Patients should be instructed to drink at least 250 mL of liquid with each dose of a bulk-forming laxative. As this level of fluid intake can be difficult for frail older persons with swallowing difficulties who drink inadequate volumes of fluid, bulk-forming laxatives may not be a good choice.

Osmotic laxatives are generally safe and effective in older persons but should not be used in patients with renal, liver, or heart failure. Emollient laxatives, specifically mineral oil, can cause lipid pneumonitis in older patients if aspirated and will decrease absorption of fat-soluble vitamins if taken chronically. For these reasons, mineral oil is not recommended as a laxative in older persons. Stool softeners, such as docusate are generally well tolerated in older persons. Saline laxatives have been associated with significant cramping, flatulence, and electrolyte disturbances. Long-term use of stimulant laxatives is not recommended as they become habit-forming, and have been associated with electrolyte disturbances.

Lubiprostone causes a dose-dependent nausea, which is offset somewhat by ingesting with food. Methylnaltrexone is generally well tolerated with abdominal pain, flatulence, nausea, dizziness, and diarrhea reported in greater than 5% of patients.

Magnesium citrate and magnesium hydroxide (MOM) should be used with caution in patients with mild to moderate renal impairment, whereas sodium phosphate is contraindicated. In patients with severe renal impairment (CrCl <30 mL/min) sorbitol, magnesium citrate, and MOM are contraindicated.

Antiemetics

Older persons can have symptoms of nausea and vomiting caused by medications, cancer, other illnesses, and constipation. When known, the choice of antiemetic can be selected by the receptor associated with the potential cause. For example, prokinetic agents (ie, metoclopramide) can be prescribed for gastric stasis, a neuroleptic for drug-induced nausea, an antihistamine for motion sickness, and a benzodiazepine for anticipatory nausea. However, empiric drug selection can be equally effective as many older persons are unable to provide a cause or describe their symptomatology in specific terms. Drug-related causes should be investigated and offending agents discontinued whenever possible.

Dopaminergic agents, like haloperidol, are effective for treating intractable nausea and vomiting and in opioid-associated nausea. Phenothiazines, such as prochlorperazine or chlorperazine, are useful for patients with nausea as a result of intestinal obstruction. Anticholinergic agents for nausea that also decrease secretions include hyoscyamine or scopolamine. However, the greater the anticholinergic effects, the more likely the agent will produce unwanted side effects in older persons. Metoclopramide, which has anticholinergic and dopaminergic effects, also inhibits serotonin receptors at higher doses.

Serotonin receptor antagonists, ondansetron, granisetron, and dolasetron have well-defined roles in postoperative nausea and vomiting as well as radiation-induced nausea. They can be used alone or combined with corticosteroids, such as dexamethasone for treating chemotherapy-induced nausea and vomiting. Corticosteroids can be effective in treating nausea related to bowel obstruction. Because dexamethasone lacks mineralocorticoid properties, it is the preferred corticosteroid for older persons.

In older persons many antiemetic agents are associated with undesirable consequences. Benzodiazepines can impair cognitive function and have been associated with hip fracture. Dosage reduction is recommended for older persons with hepatic impairment for all benzodiazepines except lorazepam, oxazepam, and temazepam, which undergo glucuronidation. In older persons, metoclopramide is associated with dyskinesia, anxiety, depression, insomnia, hallucination, fatigue, drowsiness, tremor, and restlessness. If metoclopramide is prescribed, The Abnormal Involuntary Movement Scale should be used for monitoring therapy. Metoclopramide dosage reduction is recommended in persons with renal impairment (ClCr <40 mL/min). Anticholinergic agents, like scopolamine or hyoscyamine, are associated with constipation, dry mouth, blurred vision, urinary retention, drowsiness, and tachycardia and are poor choices in older persons.

Antidiarrheals

None-infectious diarrhea can be treated safely and effectively with bismuth subsalicylate or loperamide in older persons because of the favorable safety profile. Loperamide should be avoided when there are features of mucosal involvement such as bleeding and if diarrhea induced by C difficile is suspected. Loperamide can cause central nervous system effects in patients with hepatic impairment and causes spasm of the sphincter of Oddi, thereby increasing serum amylase and lipase concentrations in some patients. Antiperistaltic agents, such as diphenoxylate, can produce nausea, lightheadedness, confusion, and sedation, and should not be used in persons with infectious diarrhea. Diphenoxylate is contraindicated in persons with jaundice or hepatic impairment. Bismuth subsalicylate is effective in the treatment of nonspecific causes of diarrhea. The salicylate component of bismuth subsalicylate can be absorbed in sufficient quantities to cause bleeding and should not be combined for more than a day or two with salicylate therapy without monitoring serum concentrations of salicylate. Opium and paregoric are considered unacceptable for use in older persons because of the potential for adverse central nervous system effects.

Possible drug-related causes of diarrhea should be investigated and alternative medications selected whenever possible.

Antispasmodics

Antispasmodics are still in widespread use in nursing home residents despite cautions against their use. “Antispasmodic drugs are poorly tolerated by elderly patients, since they cause anticholinergic adverse effects, sedation, and weakness. Additionally, their effectiveness at doses tolerated by older persons is questionable.” For these reasons belladonna alkaloids, hyoscyamine, dicyclomine, and propantheline are considered unacceptable for use in older persons.

Benzodiazepines are used as antispasmodics in persons with GI cramping, nausea, and diarrhea. However, long-acting benzodiazepines, such as chlordiazepoxide have been associated with hip fracture and because they accumulate even in short-term use, contribute to confusion and cognitive decline in susceptible patients. There are no safe alternatives to these medications in older persons.

Proton Pump Inhibitors

Proton pump inhibitors are generally considered safe and effective in older persons. Common adverse effects include headache, diarrhea, nausea, flatulence, and abdominal cramps. More serious consequences can occur with long-term administration of proton pump inhibitors. In a matched case-control study, patients older than 50 years of age who take proton pump inhibitors for more than 1 year were found to be at increased risk of hip fracture and the effect is dose-related. The investigators found that high-dose proton pump inhibitor therapy in long-term users increased the risk for hip fracture compared with nonusers (95% confidence interval [CI] 1.80–3.9, P <.001), perhaps as a result of reduced absorption of calcium. The lowest effective dose of proton pump inhibitors is recommended in older persons. Proton pump inhibitors have been associated with causing diarrhea induced by Clostridium difficile and should only be prescribed in individuals with a clear indication and for the shortest possible duration.

There is a clear relationship between drug exposure and the pharmacodynamic response (ie, gastric acid suppression, healing) to proton pump inhibitors. Proton pump inhibitors are absorbed well and should be taken approximately 1 hour before eating. Furthermore, because they are acid labile, proton pump inhibitors are manufactured as either enteric-coated granules within a capsule or enteric-coated tablets to inhibit degradation by gastric acid. Formulations should not be crushed or chewed before administration. A rapid-dissolving form of lansoprazole and a powdered form of omeprazole are available for nasogastric tube administration.

Proton pump inhibitors are extensively metabolized by the CYP 450 enzymes, primarily CYP3A4 and CYP2C19. CYP2C19 polymorphisms can significantly affect the metabolism of omeprazole and esomeprazole. Extensive metabolizers of omeprazole may require higher doses to achieve the same pharmacologic effect that poor metabolizers achieve on standard doses. Extensive metabolizers have been identified in 18% of the Swedish and Ethiopian populations but only 4% of the Chinese population. CYP2C19 activity has been shown to decline with age, such that even among extensive metabolizers, the metabolism of omeprazole is closer to that of poor metabolizers in much younger subjects. The net effect of the variances in CYP2C19 genotype and age are likely to result in the need for standard omeprazole dosing in most patients. Those extensive metabolizers with normal or intact CYP2C19 activity may be candidates for high-dose omeprazole but dosage should be governed by clinical response to therapy. The other proton pump inhibitors are metabolized to a much lesser extent or not at all by CYP2C19 and therefore are less likely to be affected by either the rapid CYP2C19 genotype or the decline in CYP2C19 function with age.

None of the proton pump inhibitors require dosage adjustment in patients with renal impairment, whereas the dosage of pantoprazole and rabeprazole should be decreased and these drugs should be used cautiously in patients with hepatic impairment.

Histamine-2 Receptor Antagonists

Important differences exist among histamine-2 antagonists that should be considered when selecting one of these agents in older persons. Cimetidine can cause thrombocytopenia, neutropenia, bradycardia, arrhythmias, confusion, depression, and gynecomastia. Cimetidine is associated with more clinically important drug interactions than the other histamine-2 antagonists because it inhibits CYP3A4 and CYP2C19 enzymes thereby decreasing the metabolism and increasing the effect of warfarin, phenytoin, theophylline, and some benzodiazepines. For these reasons and because of the larger frequency and severity of adverse reactions, cimetidine is not recommended in the elderly. Cimetidine and ranitidine have been reported to cause dyskinesia, whereas famotidine and cimetidine can cause impotence, particularly in high doses. Ranitidine has been found to have significant anticholinergic properties that may contribute to cognitive decline, constipation, dry eyes, and urinary retention in susceptible patients. Headache occurs in 4.7% and 3% of patients treated with famotidine and ranitidine, respectively. Ranitidine may inhibit CYP isozymes but famotidine and nizatidine are not metabolized by the CYP isoenzymes and do not have an inhibitory effect on hepatic clearance of other medications. All histamine-2 antagonists can cause reversible central nervous system side effects and thrombocytopenia.

All of the histamine-2 antagonists are cleared by glomerular filtration and dose reduction, by extending the dosing interval, is recommended even in persons with mild to moderate decreases in CrCl (ie, 30–60 mL/min). With severe renal impairment (CrCl <30 mL/min) the dosing interval should be extended further, the dose decreased, and patients observed for adverse central nervous system side effects.

Laxatives

All categories of laxatives can cause bloating, flatulence, and abdominal pain. Bulk-forming laxatives (eg, psyllium, methylcellulose, and polycarbophil) can cause constipation or impaction if they are not taken with sufficient fluids. Patients should be instructed to drink at least 250 mL of liquid with each dose of a bulk-forming laxative. As this level of fluid intake can be difficult for frail older persons with swallowing difficulties who drink inadequate volumes of fluid, bulk-forming laxatives may not be a good choice.

Osmotic laxatives are generally safe and effective in older persons but should not be used in patients with renal, liver, or heart failure. Emollient laxatives, specifically mineral oil, can cause lipid pneumonitis in older patients if aspirated and will decrease absorption of fat-soluble vitamins if taken chronically. For these reasons, mineral oil is not recommended as a laxative in older persons. Stool softeners, such as docusate are generally well tolerated in older persons. Saline laxatives have been associated with significant cramping, flatulence, and electrolyte disturbances. Long-term use of stimulant laxatives is not recommended as they become habit-forming, and have been associated with electrolyte disturbances.

Lubiprostone causes a dose-dependent nausea, which is offset somewhat by ingesting with food. Methylnaltrexone is generally well tolerated with abdominal pain, flatulence, nausea, dizziness, and diarrhea reported in greater than 5% of patients.

Magnesium citrate and magnesium hydroxide (MOM) should be used with caution in patients with mild to moderate renal impairment, whereas sodium phosphate is contraindicated. In patients with severe renal impairment (CrCl <30 mL/min) sorbitol, magnesium citrate, and MOM are contraindicated.

Antiemetics

Older persons can have symptoms of nausea and vomiting caused by medications, cancer, other illnesses, and constipation. When known, the choice of antiemetic can be selected by the receptor associated with the potential cause. For example, prokinetic agents (ie, metoclopramide) can be prescribed for gastric stasis, a neuroleptic for drug-induced nausea, an antihistamine for motion sickness, and a benzodiazepine for anticipatory nausea. However, empiric drug selection can be equally effective as many older persons are unable to provide a cause or describe their symptomatology in specific terms. Drug-related causes should be investigated and offending agents discontinued whenever possible.

Dopaminergic agents, like haloperidol, are effective for treating intractable nausea and vomiting and in opioid-associated nausea. Phenothiazines, such as prochlorperazine or chlorperazine, are useful for patients with nausea as a result of intestinal obstruction. Anticholinergic agents for nausea that also decrease secretions include hyoscyamine or scopolamine. However, the greater the anticholinergic effects, the more likely the agent will produce unwanted side effects in older persons. Metoclopramide, which has anticholinergic and dopaminergic effects, also inhibits serotonin receptors at higher doses.

Serotonin receptor antagonists, ondansetron, granisetron, and dolasetron have well-defined roles in postoperative nausea and vomiting as well as radiation-induced nausea. They can be used alone or combined with corticosteroids, such as dexamethasone for treating chemotherapy-induced nausea and vomiting. Corticosteroids can be effective in treating nausea related to bowel obstruction. Because dexamethasone lacks mineralocorticoid properties, it is the preferred corticosteroid for older persons.

In older persons many antiemetic agents are associated with undesirable consequences. Benzodiazepines can impair cognitive function and have been associated with hip fracture. Dosage reduction is recommended for older persons with hepatic impairment for all benzodiazepines except lorazepam, oxazepam, and temazepam, which undergo glucuronidation. In older persons, metoclopramide is associated with dyskinesia, anxiety, depression, insomnia, hallucination, fatigue, drowsiness, tremor, and restlessness. If metoclopramide is prescribed, The Abnormal Involuntary Movement Scale should be used for monitoring therapy. Metoclopramide dosage reduction is recommended in persons with renal impairment (ClCr <40 mL/min). Anticholinergic agents, like scopolamine or hyoscyamine, are associated with constipation, dry mouth, blurred vision, urinary retention, drowsiness, and tachycardia and are poor choices in older persons.

Antidiarrheals

None-infectious diarrhea can be treated safely and effectively with bismuth subsalicylate or loperamide in older persons because of the favorable safety profile. Loperamide should be avoided when there are features of mucosal involvement such as bleeding and if diarrhea induced by C difficile is suspected. Loperamide can cause central nervous system effects in patients with hepatic impairment and causes spasm of the sphincter of Oddi, thereby increasing serum amylase and lipase concentrations in some patients. Antiperistaltic agents, such as diphenoxylate, can produce nausea, lightheadedness, confusion, and sedation, and should not be used in persons with infectious diarrhea. Diphenoxylate is contraindicated in persons with jaundice or hepatic impairment. Bismuth subsalicylate is effective in the treatment of nonspecific causes of diarrhea. The salicylate component of bismuth subsalicylate can be absorbed in sufficient quantities to cause bleeding and should not be combined for more than a day or two with salicylate therapy without monitoring serum concentrations of salicylate. Opium and paregoric are considered unacceptable for use in older persons because of the potential for adverse central nervous system effects.

Possible drug-related causes of diarrhea should be investigated and alternative medications selected whenever possible.

Antispasmodics

Antispasmodics are still in widespread use in nursing home residents despite cautions against their use. “Antispasmodic drugs are poorly tolerated by elderly patients, since they cause anticholinergic adverse effects, sedation, and weakness. Additionally, their effectiveness at doses tolerated by older persons is questionable.” For these reasons belladonna alkaloids, hyoscyamine, dicyclomine, and propantheline are considered unacceptable for use in older persons.

Benzodiazepines are used as antispasmodics in persons with GI cramping, nausea, and diarrhea. However, long-acting benzodiazepines, such as chlordiazepoxide have been associated with hip fracture and because they accumulate even in short-term use, contribute to confusion and cognitive decline in susceptible patients. There are no safe alternatives to these medications in older persons.