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
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