Minimizing Adverse Drug Events

Geriatric patients often have multiple chronic medical conditions and are, therefore, prescribed numerous medications for medical management. Whenever possible, non-pharmacologic interventions should be used prior to the initiation of medications.

A drug is defined as any administered substance that alters normal bodily function. An adverse drug event is any noxious, unintended, and undesired effect of a drug which occurs at doses used for prophylaxis, diagnosis, or therapy. Polypharmacy is a pattern of excessive and inappropriate use of prescription and non-prescription medications; more than five medications is considered polypharmacy.

Risks for adverse drug events include:

• 6 or more concurrent chronic medical conditions
• 12 or more medication doses per day
• 5 or more prescribed or non-prescribed medications
• prior adverse drug events
• low body weight or BMI
• age over 80
• creatinine clearance less than 50 mL/min

Over 35% of geriatric patients have adverse drug events annually, and over 50% of these events are preventable and predictable. Up to one-third of hospital admissions can be attributed to adverse drug events.

Drug-drug interactions are the clinical response of combinations of drugs that differ from anticipated effects compared to if the drugs are administered separately; that is, how drugs interact with other drugs. Drug-drug interactions increase with increasing number of drugs, are most commonly seen between cardiovascular and psychotropic drugs, and include confusion, hypotension, and renal failure.

Examples of drug-drug interactions include:

• Warfarin plus NSAIDs or antibiotics can lead to elevated INR values
• ACE (angiotensin converting enzyme) inhibitors plus potassium supplements, spironolactone, or NSAIDs can increase the risk of hyperkalemia
• Digoxin plus amiodarone leads to increased digoxin levels due to amiodarone inhibiting the cytochrome P450 system
• Digoxin plus verapamil contributes to an increased risk of heart block
• Antipsychotic agents with or without fluoroquinolones can increase the QT interval and also be associated with sudden death
• Clopidogrel plus proton-pump inhibitors has been shown to increase incidence of cardiovascular events (such as MI, CVA, etc.)

Prescribing cascades occur when side effects of drugs are misdiagnosed as symptoms of another problem, resulting in further prescriptions and further side effects along with unanticipated drug interactions, which may lead to further misdiagnosis and further symptoms.

Non-steroidal anti-inflammatory drugs (NSAIDs) can lead to dyspepsia, elevated blood pressure, and peripheral edema. By inhibiting prostaglandin synthesis, NSAIDs can cause dyspepsia. Elevated blood pressures occur as a result of afferent vasoconstriction in the glomerulus of the nephron, leading to increased renin secretion, ultimately leading to increased angiotensin production and vasoconstriction. Peripheral edema occurs as a result of increased sodium reabsorption as a result of inhibiting prostaglandin synthesis. With the appearance of these new symptoms, physicians may be tempted to prescribe omeprazole (for dyspepsia symptoms), lisinopril (for elevated blood pressure), and furosemide (for peripheral edema).

To summarize, the effects of NSAIDs on renal function include:

1. Afferent arterioles are constricted
2. Efferent arterioles are dilated
3. Decreased filtration fraction
4. Juxtaglomerular apparatus senses decreased filtration fraction and triggers renin release and fluid-retaining mechanisms
5. Increased angiotensin synthesis causes hypertension

Corticosteroids can lead to hyperglycemia (stimulating hepatic gluconeogenesis), elevated blood pressures (due to mineralocorticoid effects mimicking aldosterone), and dyspepsia (due to inhibition of prostaglandin synthesis). Therefore, physicians may prescribe glucose-lowering medications, anti-hypertensives, and proton-pump inhibitors to treat these side effects.

Calcium-channel blockers, such as amlodipine, cause peripheral edema (due to vasodilation of blood vessels, allowing third-spacing of fluid), urinary incontinence (due to decreased smooth muscle contractility in the bladder), psychosis (due to interference with mood regulation), parkinsonism (reversible with stopping the drug, mechanism unclear), and hypotension (due to excessive vasodilation). Physicians may feel compelled to prescribe medications, respectively, such as furosemide, oxybutynin (an anticholinergic medication), risperidone (an anti-dopaminergic medication), carbidopa/levodopa (to increase dopamine availability in the brain), and midodrine (for hypotension).

Drug-disease interactions are important to consider because drugs that are helpful in one disease may be harmful in another disorder. For example, a patient may be prescribed a beta blocker for a cardiac disease. While this may be helpful in lowering blood pressure or heart rate, it can worsen reactive airway disease (i.e. asthma) symptoms and also make it more difficult for diabetics to sense hypoglycemia. Also, beta blockers can cause or worsen depression symptoms. Specific drug-disease interactions include obesity, ascites, dementia, renal disease, and liver disease. Obesity alters the volume of distribution of lipophilic drugs. Ascites alters the volume of distribution of hydrophilic drugs. Renal disease and liver disease reduce the non-renal clearance and alter bioavailability of drugs predominantly metabolized by the liver and intestine.

Examples of drug-disease interactions include:

• Congestive heart failure interactions with NSAIDs, thiazolidinediones, and sodium-containing medications can all lead to increased fluid retention
• Peptic ulcer disease interactions with NSAIDs, high-dose aspirin cause inhibition of prostaglandin synthesis and worsen peptic ulcer disease and increased risk of GI bleeding
• COPD interactions with long-term benzodiazepines have increased risk of confusion and respiratory depression
• Diabetes mellitus interactions with long-acting sulfonylureas can cause hypoglycemia
• Hypertension interactions with pseudoephedrine and amphetamines can exacerbate elevated blood pressures
• Cognitive impairment interactions with anticholinergics, antispasmodics, muscle relaxants, and CNS stimulants can all lead to increased confusion
• Urinary incontinence interactions with anticholinergic effects leading to urinary retention
• Parkinson’s disease interactions with dopamine antagonists and metoclopramide can cause parkinsonism and tardive dyskinesias as well as exacerbate Parkinson's disease symptoms (i.e. tremors)
• Falls/Syncope interactions with tricyclic antidepressants and benzodiazepines increase risk of the same
• Chronic constipation interactions with calcium-channel blockers, anticholinergics, and tricyclic antidepressants lead to worsening of constipation

Supplements include vitamins, minerals, herbs, and other natural products. Supplements are not subject to development and approval processes by the Food and Drug Administration (FDA). Some supplements can play an important role in health. For example, calcium and vitamin D supplements are useful for bone health and are often prescribed for patients with osteoporosis. Other supplements have not been studied extensively nor has their perceived benefit been proven by research. Supplements may also contribute to adverse drug events.

Common supplements with side effects that must be considered in geriatric patients are:

• Gingko biloba: Apparent benefits are to improve blood circulation, oxygenation, and memory and alertness. Side effects include increasing bleeding risk, particularly in patients taking aspirin or warfarin.
• Saw palmetto: Apparent benefits for enlarged prostate and urinary problems. Side effects include interference with other hormonal therapies.
• St. John’s wort: Apparent benefits are for mild-to-moderate depression symptoms, anxiety symptoms, or insomnia symptoms. Side effects include interaction with other drugs such as sedatives, verapamil, warfarin, and selective-serotonin re-uptake inhibitors (SSRIs)
• Garlic: Apparent benefits are for lowering cholesterol. Side effects include interactions with other drugs.

By illustrating the potential catastrophes associated with prescribing cascades, it is important for physicians to establish the correct diagnosis for which a medication is being prescribed, determine if pharmacologic treatment is necessary, consider drug-drug interactions, and stopping or reducing the dose of the most recent causative agent.

A frequently used phrase by geriatricians (and members of other specialties) is to “start low and go slow” when prescribing a new medication, particularly to a geriatric patient, and to consider gradual dose reductions of medications in order to reduce side effects and adverse drug events. Another contributing factor to prescribing cascades and polypharmacy is physicians (i.e. the primary care physician and any specialists) who do not communicate with each other. Frail older adults often have decreased cholesterol levels. As such, lipid-lowering medications should not be prescribed to patients with a limited life expectancy as they also contribute to polypharmacy.

Aging and Pharmacology

Age-related biological and physiological changes must be considered for older adults when prescribing medications. Pharmacodynamics and pharmacokinetics are subject to age-related changes.

Pharmacokinetics is the branch of pharmacology that deals with the movement of drugs throughout the body and metabolism; specifically, age-related changes can affect absorption, first-pass effects, distribution, metabolism, elimination (used interchangeably with excretion), and clearance.

With regard to absorption, the movement of a drug from the site of administration to the blood, decreases in absorptive surface splanchnic blood flow, increases in gastric pH, and slowed gastrointestinal motility are issues that must be considered. The most common methods of administration of drugs are orally (PO, meaning per os in Latin, or “by way of the opening”), intravenously (IV), intramuscularly (IM), or subcutaneously (SQ) in adipose tissue just under the skin. There is no significant change in absorption associated with normal aging, though there may be a delay in time needed to see an effect due to the number and type of medications taken.

Distribution describes the reversible transfer of a drug from one location to another (such as from the gastrointestinal tract to the systemic circulation). With aging, there is a decrease in lean body mass and serum albumin (the major drug-binding protein), increased adipose tissue, and altered protein binding affecting the volume of distribution (V_D). Water-soluble drugs become more concentrated in the serum as a result; fat-soluble drugs will have longer half lives (such as benzodiazepines, for example).

With respect to the first pass effect (the reduction in the concentration of a drug before it reaches the systemic circulation) and metabolism, the enzymatic breakdown and biotransformation of drugs, decreases in hepatic blood flow, enzyme activity, and enzyme inducibility should be considered. Phase 1 metabolism (i.e. oxidation) is inhibited in the cytochrome P450 system (and its subsets such as CYP3A and CYP2D6) by medications such as amiodarone, SSRIs, and fluoroquinolones and induced by anti-epileptic drugs such as phenytoin.

Consideration of elimination, or the excretion of a drug, changes in renal function, described in the coming pages, plays a significant role in pharmacokinetics. It is quite often difficult to predict for individuals how each of these processes is affected, but general principles can be applied in this discussion. Renal function decreases by approximately 1% per year after age 40.

Pharmacodynamics is the branch of pharmacology concerned with the effects of drugs and their mechanism of action; age-related concerns include therapeutic dosing and effects and side effects. Pharmacodynamic considerations include:

• Blunted baroreceptor reflexes due to orthostatic hypotension leading to an increased risk of syncope and falls
• Decreased beta adrenoreceptor responsiveness
• Decreased dopaminergic receptors in the central nervous system (i.e. seeing parkinsonism with haloperidol)
• Increased inhibitory effects of warfarin
• Increased sensitivity to the anticholinergic effects of drugs that contributes to increased risk of delirium and urinary retention
• Increased central nervous system effect of benzodiazepines, opioids, and psychotropics will contribute to increased risk of falls, confusion, and delirium

Renal clearance plays a role in drug metabolism. Both glomerular filtration rate (GFR) and creatinine clearance (CrCl) are measurements of kidney function. Though similar, these two quantities should be treated distinctly. GFR and CrCl are not identical quantities! Decreased muscle mass (i.e. sarcopenia) in geriatric patients decreases serum creatinine.

Creatinine clearance can be calculated using the Cockcroft-Gault equation:

${\displaystyle CrCl(male)={\frac {(140-age)(weightinkg)}{(72)(serumCrinmg/dL)}}}$

${\displaystyle CrCl(female)=(0.85)(CrCl(male))}$

Glomerular filtration rate (GFR) is calculated using a complex equation known as the MDRD equation (Modification of Diet in Renal Disease). This equation considers sex, race (African-American vs. non-African-American), age, and serum creatinine; this will not be covered here. The estimated GFR (or eGFR) is often provided on laboratory studies such as a Basic Metabolic Panel (BMP) or Renal Function Panel (RFP).

Chronic kidney disease is staged by GFR levels for at least 3 months. Otherwise, decreased GFR and elevated creatinine are attributable to acute kidney injury which should resolve in a short period of time. Chronic kidney disease (CKD) is often associated with long-standing hypertension and can be more correctly described as hypertensive kidney disease.

To classify the extent of chronic kidney disease, GFR is used:

• CKD stage 1 occurs when GFR is greater than 90
• CKD stage 2 occurs when GFR is between 60-90
• CKD stage 3 occurs when GFR is between 30-60 (This can be split into 3A/3B, but this is not considered in this discussion.)
• CKD stage 4 occurs when GFR is between 15-30
• CKD stage 5 (end-stage renal disease) occurs when GFR is less than 15

Chronic kidney diseases stage 1 and 2 are not necessary to consider in geriatric patients. A majority of patients over the age of 65 have chronic kidney disease stage 3 or beyond. Chronic kidney disease stage 5 is synonymous with end-stage renal disease (ESRD) which will eventually require hemodialysis, peritoneal dialysis, or renal transplantation. However, the decision to proceed with either peritoneal dialysis or hemodialysis should be in alignment with the patient’s desires and preferences. Hemoglobin levels are also reduced as a result of decreased erythropoietin production. This will be discussed in more detail in subsequent chapters. Expected symptoms include fatigue and shortness of breath secondary to anemia (specifically, anemia of chronic disease, or, more specifically, anemia of chronic kidney disease).

Potentially-Inappropriate Medications

There are three sources geriatricians commonly consult when deciding to prescribe new medications. These sources include:

• American Geriatrics Society Beers Criteria for Potentially Inappropriate Medication Use in Older Adults - Beers list
• START criteria (Screening Tool to Alert doctors to Right Treatment)
• STOPP criteria (Screening Tool of Older Person’s Prescriptions)

These sources should not be memorized but rather understood in terms of the appropriateness of prescribing medications. Potentially inappropriate does not mean do not use; it means use with caution and look for alternatives whenever possible due to concern about side effects.

Some examples of potentially inappropriate medications include:

• Muscle relaxants: carisoprodol, cyclobenzaprine, and metaxalone
• Sedatives/Anxiolytics/Hypnotics: benzodiazepines such as alprazolam, diazepam, and chlordiazepoxide
• Anti-depressants: amitriptyline
• Anti-histamines: diphenhydramine, hydroxyzine, promethazine (all first generation)
• Anti-hypertensives: nifedipine
• Anti-cholinergics: oxybutynin, dicyclomine, and hyoscyamine
• Analgesics: NSAIDs, opioids
• Others: barbiturates, nitrofurantoin (if CrCl < 30)

To Prescribe or Not to Prescribe?

Consider the following medications:

• Proton-pump inhibitors: if required longer than six weeks, should be referred to gastroenterology for further workup
• Benzodiazepines: use only in the short-term if possible; use short-acting benzodiazepines such as alprazolam or lorazepam as opposed to diazepam when possible
• Tricyclic antidepressants: have anti-cholinergic properties, don’t use for depression if SSRIs are an option
• Anti-psychotics: not approved for Alzheimer’s disease but are frequently used for agitation (will discuss in more detail in Chapter 5)
• Sedatives/Hypnotics: trazodone only; avoid zolpidem
• Beta-blockers: only in cardiac diseases, avoid in COPD
• Pain medications: tramadol precipitates seizures; opioids cause constipation and confusion
• NSAIDs: increase renal issues and fluid retention
• Digoxin: keep at sub-therapeutic levels to prevent toxicity for patients with cardiac arrhythmias
• Oxybutynin: anticholinergic effects
• Stool softeners: always prescribe with opioid pain medications (will discuss in more detail in Chapter 12); prescribe in this order until effectiveness is achieved:

1. senna/docusate (together)
2. miralax
3. lactulose
4. enema

• Tamsulosin/Finasteride: tamsulosin works immediately but can cause orthostatic hypotension; finasteride takes about 6 months to work
• Megesterol: can cause deep venous thromboses (DVTs; i.e. blood clots in the lower extremities); use mirtazapine for appetite stimulation first
• Aromatase inhibitors: can cause DVTs (i.e. tamoxifen)
• Statins: require at least 2 years for primary prevention and 5 years for secondary prevention of cardiovascular disease; can discontinue in patients with limited life expectancy
• Diabetes medications Chapter 11:
  • Sulfonylureas: precipitate hypoglycemia
  • Thiazolidinediones: CHF/fluid retention
  • DPP4-inhibitors: CHF/fluid restriction
  • Metformin and sitagliptin are acceptable (no metformin if serum Cr > 1.5 mg/dL)

Review Questions

1. An 86-year-old male is hospitalized following a left hip fracture after a fall. She undergoes an elective left hip open reduction with internal fixation and placement of a long cephalomedullary nail. On post-operative day 2, she complains of abdominal pain that she attributes to not having a bowel movement since the procedure. Her vital signs and physical exam are unremarkable. Rectal exam reveals an absence of fecal impaction. Abdominal X-ray shows a large bowel burden but no evidence of ileus. Which of the following medication(s) is first line for the treatment of this patient?

A. Miralax
B. Bisacodyl
C. Lactulose
D. Metoclopramide
E. Senna and docusate

2. Which antibiotic for the treatment of urinary tract infections is considered potentially inappropriate based on the Beers list of potentially inappropriate medications?

A. Amoxicillin
B. Nitrofurantoin
C. Doxycycline
D. Ciprofloxacin
E. Trimethoprim/Sulfamethoxazole

3. Which of the following does not affect the calculation of the creatinine clearance according to the Cockcroft-Gault equation?

A. Age
B. Weight
C. Sex
D. Serum creatinine
E. Glomerular filtration rate

4. How do non-steroidal anti-inflammatory medications (NSAIDs) affect renal blood flow?

A. NSAIDs cause vasodilation of the efferent arteriole.
B. NSAIDs cause vasoconstriction of the efferent arteriole.
C. NSAIDs cause vasodilation of the afferent arteriole.
D. NSAIDs cause vasoconstriction of the afferent arteriole.
E. NSAIDs have no effect on renal blood flow.

5. A 76-year-old male presents to his primary care physician at the urging of his son for evaluation of frequent falls. He notes that he has been falling frequently. The falls are occurring at all times of the day. He notes that he feels dizzy sometimes immediately upon standing up. He has not been started on any new medications recently. He denies any head injury or loss of consciousness. He states that the symptoms began approximately four months ago. His medications include amlodipine 5 mg 1 tab daily, hydrochlorothiazide 12.5 mg 1 tab daily, lisinopril 2.5 mg 1 tab daily and metformin 500 mg 1 tab with breakfast and dinner. His vital signs show a blood pressure of 130/80 seated, which drops to 100/68 upon standing; heart rate of 75 seated which increased to 90 standing; temperature of 98.8 F, respiratory rate of 18, and oxygen saturation of 97%. His physical exam is notable for bruises at mild stages of resolving all over his body including on his head, chest, arms, back, and legs. His neurologic exam is unremarkable. He does show +2 bilateral lower extremity edema. The remainder of the physical exam is unremarkable. Which of the following medications would be most appropriate to stop at this time?

A. amlodipine
B. hydrochlorothiazide
C. lisinopril
D. metformin
E. No medications should be stopped at this time

6. Which of the following medications is potentially inappropriate?

A. A 78-year-old male with end-stage renal disease on lisinopril
B. A 99-year-old female with hyperlipidemia and no other cardiovascular or peripheral vascular disease on atorvastatin
C. An 85-year old male with peptic ulcer disease and a history of upper GI bleeds on omeprazole
D. A 79-year-old female with adult failure to thrive syndrome on mirtazapine
E. An 86-year-old female with a coronary artery disease, history of NSTEMI, and atrial fibrillation who is on hospice on aspirin 325 mg daily

Answers to Review Questions

1. E
2. B
3. E
4. D
5. A
6. B