Download CE Activity

Download CE Activity

Download CE Activity

INTRODUCTION

Did the Mona Lisa have hypothyroidism? Discussions around the Mona Lisa’s enigmatic smile have fascinated art lovers for centuries but now some endocrinologists have started a new line of debate. They describe telltale signs, like swollen hands, thinning hair, and a lump in the neck, that point to the famous Mona Lisa exhibiting hypothyroidism. They even suggest that the disease contributed to her mysterious smile. Amusing! When you view the painting do you see the same signs?

 

Theodor Kocher, a Swiss physician who was award the Nobel Prize in 1909 for his work on the thyroid gland, described the first case of hypothyroidism in the mid-19^th century.¹ Effective treatment emerged about 100 years ago, so if the 16^th century Mona Lisa had hypothyroidism, she might have suffered without knowing the cause. Patients with undiagnosed or inadequately treated hypothyroidism are at risk for cardiovascular problems, osteoporosis, and infertility.²

 

The thyroid gland’s main hormones are responsible for controlling the body’s energy production and metabolic rate and they affect nearly every organ system in the body. Having too little or too much of these hormones can have profound consequences on health.

 

Millions of Americans are affected by thyroid disease with most cases classified as hypothyroidism or underactive thyroid. Children, whose cognitive and physical development depends on normal thyroid function, can also be affected.³ Levothyroxine is used to treat hypothyroidism and is consistently among the most frequently prescribed medications in the United States (U.S.).⁴ Although less common, hyperthyroid disease is a serious endocrine disorder with profound health consequences if not properly treated.

 

THYROID GLAND AND FUNCTION

The thyroid gland is a small bow tie shaped endocrine gland that sits at the base of the neck. It produces two main hormones: tetraiodothyronine called thyroxine (T4), and triiodothyronine (T3). T4 and T3 control energy production and metabolic rate and influence nearly every organ system in the body including the brain, bowels, and skin. They regulate protein, carbohydrate, and fat metabolism by stimulating protein production and increasing oxygen needs at the cellular level. They are essential for proper fetal and neonatal development. Thyroid hormones influence body temperature, heart rate, appetite, mood, and digestion.²

 

Iodine is a constituent of T4 and T3 and sufficient dietary intake of iodine and its adequate uptake by the thyroid gland is necessary for proper thyroid function. The thyroid gland produces mostly inactive hormone in the form of thyroxine, called T4 because it has four iodine atoms. T4 is highly protein bound for transport to the liver where it undergoes deiodination (the removal of one iodine atom) resulting in T3. T3, like T4, is highly protein bound and must be released from its binding protein to be active. Equilibrium is maintained between bound and free T3; as the body demands more biologically active hormone more T3 is released from the binding protein. Free T3 is the main biologically active form of thyroid hormone.²

 

Hypothalamic-Pituitary-Thyroid Axis

The hypothalamic-pituitary-thyroid axis governs thyroid hormone production by regulating the synthesis and secretion of thyroid stimulating hormone (TSH), also called thyrotropin. The hypothalamus is the part of the brain responsible for monitoring thyroid hormone levels in the body. When the hypothalamus detects low levels of thyroid hormone in the body, it releases a hormone called thyrotropin-releasing hormone (TRH). TRH stimulates the pituitary gland, the small pea-size gland sitting at the base of the brain, to secrete TSH. TSH, in turn, instructs the thyroid gland to produce more T4 and T3. High levels of T4 in the body inhibit TSH secretion while low levels of T4 stimulate TSH secretion. Disease affecting any part of the hypothalamic-pituitary-thyroid axis can result in thyroid hormone imbalances and disease.²

 

THYROID DISEASE AND ETIOLOGY

Thyroid disease is an endocrine disorder. Primary thyroid disease refers to disease of the thyroid gland. Secondary thyroid disease is far less common and refers to disease affecting the hypothalamus or pituitary gland resulting in thyroid dysfunction. Thyroid disease is classified as either hypothyroidism or hyperthyroidism.

 

Hypothyroid Disease

Hypothyroid disease occurs when inadequate thyroid hormone is available to the body. It is often referred to as an underactive thyroid and it is the most common form of thyroid disease. Hypothyroid disorders are categorized as either primary hypothyroidism or secondary hypothyroidism. The vast majority of cases are primary hypothyroidism.²

 

Hashimoto’s Thyroiditis

Hashimoto’s thyroiditis (HT) is the most common cause of primary hypothyroidism in the U.S. Japanese physician Hakaru Hashimoto first described the disease in 1912. It wasn’t until decades later that it was recognized as an autoimmune disorder and it is now considered the most prevalent autoimmune disease.⁵ Many patients do not realize that their hypothyroid condition is caused by this autoimmune disorder.

 

HT is characterized by infiltration and destruction of thyroid cells by leukocytes (white blood cells). A chronic autoimmune inflammation ensues resulting in atrophy and fibrosis of the thyroid gland that leads to hypothyroidism. Circulating thyroid autoantibodies, anti-thyroperoxidase antibody (anti-TPO Ab), and anti-thyroglobulin antibody (anti-Tg Ab) can be detected but clinicians usually don’t measure them since all treatment of hypothyroidism is similar.⁶

 

Women are more likely to develop HT and often have a family history, implicating a genetic component. The presence of other autoimmune disorders is common and prevalence is higher among those with chromosomal disorders like Down syndrome.²

 

Patients may present with thyroiditis (inflammation of the thyroid gland) and symptoms of hypothyroidism, like weight gain and fatigue, but not always. Symptoms can develop gradually and go unnoticed. Laboratory assessment of thyroid function (discussed below) confirms the diagnosis. Individuals diagnosed with HT require lifelong treatment with the thyroid replacement hormone levothyroxine.⁶

 

HT’s complications can manifest particularly in untreated or undertreated individuals including²:

• Lipid disorders (elevated total cholesterol, LDL, and triglycerides)
• Anemia
• Menstrual abnormalities
• Infertility
• Hyponatremia
• Thyroid associated orbitopathy
• Increased risk for papillary thyroid carcinoma

 

Lipid disorders are of particular concern because they can contribute to coronary artery disease. Anemia is observed in 30% to 40% of patients. Recent research has suggested greater risk for recurrent pregnancy loss in patients with HT and an additional autoimmune disorder, but more research is needed to fully understand the link.⁷

 

Most complications of HT are rare but prescribers must monitor and treat complications as they arise to optimize patient management.⁸

 

Researchers have also noted vitamin D deficiency in HT. A randomized, double blind, clinical trial observed that supplementation with vitamin D reduced circulating thyroid autoantibodies.⁵ The researchers suggest a possible role for vitamin D in the alleviation of disease activity but acknowledge the need for further studies before introducing this intervention to clinical practice. Despite the need for additional research, treating vitamin D deficiency in patients with HT may be warranted.

 

Gut microbiota are considered intrinsic regulators of thyroid autoimmunity. Scientists have studied the composition of the microbiota in patients with thyroid autoimmunity and have found it to be altered in HT.⁹ Clinical implications of this research are not fully understood, but further research may determine the role these findings may have in HT management.

 

With early diagnosis, prompt treatment, proper follow-up care, and attention to associated complications, HT’s prognosis is excellent, and patients lead a normal life.¹⁰

 

Iodine Deficiency Hypothyroidism

Although uncommon in America, iodine deficiency is the leading cause of hypothyroidism worldwide. Adequate iodine intake is necessary for the thyroid gland to function properly, and it is critical for normal fetal and neonatal development. The recommended daily allowance (RDA) for adults is 150 mcg and it increases to 250 mcg in pregnancy and to 290 mcg during lactation. Goiter (an abnormal enlargement of the thyroid gland) is common as the thyroid gland enlarges in an attempt to sequester iodine to make thyroid hormone.^11,63

 

Universal salt iodization programs have dramatically reduced iodine deficiency-related thyroid disease.¹² Historically, iodine deficient areas in the U.S. included the mountainous regions and the so called “goiter belt” around the Great Lakes. Most Americans now consume adequate amounts of iodine in their diets by using iodized salt and by eating dairy products, eggs, and seafood. However, certain populations may still be at risk, including vegans, pregnant women, and people who don’t use iodized salt.¹¹ Most alternative milk products are low in iodine and processed foods like canned soup and specialty salts–including kosher, Himalayan, and sea salt–rarely provide iodine.¹³ Healthcare practitioners must be aware of iodine deficiency’s consequences, especially during pregnancy.^11,63

 

Thyroid diets have gained interest among patients and circulate widely on the Internet. These diets promote avoiding particular foods to achieve optimal thyroid function. Certain foods including broccoli, Brussels sprouts, cabbage, cauliflower, and soy contain goitrogens, which are substances that interfere with iodine uptake by the thyroid. For most people in the U.S. who consume adequate amounts of iodine, eating foods containing goitrogens is not a concern. People with iodine deficiency who eat an abundance of these foods may have trouble consuming enough iodine.^13,63

 

Thyroidectomy and Cancer Treatment Resulting in Hypothyroidism

Thyroidectomy, the surgical removal of the thyroid gland, is sometimes indicated in cancer treatment and in some cases of hyperthyroidism. Thyroidectomy results in hypothyroidism and patients require life-long thyroid hormone replacement with levothyroxine.¹⁴

 

Most thyroid cancers respond well to treatment, but a small percentage can be very aggressive. Treatment of thyroid cancer often results in hypothyroidism and patients require lifelong treatment with thyroid replacement hormone.¹⁴

 

Medication-Induced Hypothyroidism

The pharmacy team must be aware that certain medications can affect thyroid function. Table 1 lists common medications that can cause hypothyroidism and hyperthyroidism. The medications that cause hypothyroidism decrease synthesis of T4/T3, inhibit T4/T3 secretion, and/or cause thyroiditis.¹⁵

 

Table 1. Medications that May Lead to Thyroid Dysfunction
Drug class/medications	Hypothyroidism	Hyperthyroidism
Antidysrhythmic:
Amiodarone	X	X
Bipolar Disorder Medication:
Lithium	X	X
Thyroid Medications:
PTU	X
Methimazole	X
Radioactive Iodine	X
Cancer Medications:
Biological response modifiers:
Interferon	X
Interleukin-2	X
Tyrosine kinase inhibitors:
Sunitinib	X
Sorafenib	X
Checkpoint inhibitors:
Nivolumab	X	X
Pembrolizumab	X	X
Ipilimumab	X	X
Multiple Sclerosis Medication:
Alemtuzumab		X

 

Medications that cause thyroid disorders are important treatments and, in most cases, they cannot be discontinued; any drug-induced hypothyroidism requires levothyroxine.

 

Amiodarone structurally resembles thyroid hormone and is often implicated in thyroid dysfunction, mostly hypothyroidism.¹⁶ It is comprised of 37% iodine, so a 200 mg dose provides 75 mg of organic iodide, which is 100 times more than required. Researchers estimate thyroid abnormalities occur in 14% to 18% of patients taking long-term amiodarone but a meta-analysis found that with low doses, the incidence is lower (3.7%).¹⁷ Lithium can inhibit thyroid hormone release resulting in hypothyroidism; it usually occurs in younger women within the first two years of therapy. Antineoplastic agents may cause thyroid dysfunction in 20% to 50% of patients.¹⁸ Pharmacists must educate patients about the need for routine thyroid function assessment when receiving these medications.

 

Hyperthyroid Disease

Hyperthyroidism is characterized by excessive metabolism and secretion of thyroid hormones. It is less common than hypothyroid disease. Graves’ disease, thyroiditis, multi-nodular goiter, and toxic nodular goiter (benign growths on the thyroid gland that produce thyroid hormone in excess) can also cause hyperthyroid disease. Ingestion of too much external thyroid hormone is another possible cause of hyperthyroidism.¹⁹

 

Graves’ Disease

Graves’ disease (GD) accounts for most cases of hyperthyroidism. GD is an autoimmune disorder caused by a stimulatory autoantibody against the thyroid receptor for TSH. Most autoantibodies are inhibitory; in GD, the autoantibody is stimulatory. Overstimulation of the thyroid gland results in the overproduction of T4 and T3 leading to hyperthyroidism.¹²

 

Graves’ disease, like HT, appears to have a genetic link and is often comorbid with other autoimmune disorders. Risk factors for GD include smoking and iodine deficiency. In the case of iodine deficiency, multifocal autonomous growth of the thyroid gland can occur and result in thyrotoxicosis (excess levels of thyroid hormone in the body).²⁰ Women are affected at a higher rate and children can also be affected. GD’s clinical presentation may be dramatic or subtle and goiter may or may not be present. Laboratory assessment of thyroid function is used to help diagnose GD.

 

Researchers have studied the composition of gut microbiota in patients with GD and similar to findings in HT, have found it to be altered. The researchers suggest the findings from this randomized controlled trial may offer an alternative noninvasive diagnostic methodology for GD.²¹ Further research is needed to elucidate the role microbiota may play in thyroid autoimmunity.

 

Thyroid Eye Disease

Thyroid eye disease is a progressive, potentially sight threatening ocular disease that is reported in almost half of patients who have GD. It arises from a separate autoimmune process involving autoantibodies that activate an insulin-like growth factor-1 receptor (IGF-1R) mediated signaling complex on cells within the eye orbit. The most common clinical feature is proptosis (bulging eyes) with edema and erythema of the surrounding eye tissue, but patients may also experience a skin manifestation called thyroid dermopathy (a nodular diffuse thickening of the skin on the legs). Patients with thyroid eye disease often complain of dry and gritty ocular sensation, photophobia, excessive tearing, double vision, and pressure sensation behind the eyes. Severe disease occurs in 3% to 5% of patients causing intense eye pain and inflammation, and threatening sight.²²

 

Recently, the Food and Drug Administration (FDA) approved the monoclonal antibody teprotumumab for treatment of adults with thyroid eye disease, marking a significant advancement in treatment. Prior to this approval, treatment options only included steroids or surgery.²³

 

Medication Induced Hyperthyroidism

Like medication that can cause hypothyroidism, some medication can cause hyperthyroidism. The pharmacy team must be knowledgeable of the medications that can cause hyperthyroidism that warrant close monitoring of thyroid function (See Table 1). Patients should understand the importance of routine thyroid function assessment when taking medications that can affect thyroid function.

 

Amiodarone-associated hyperthyroidism is less common than amiodarone-associated hypothyroidism; still, it is estimated to occur in 3% of patients. Onset of amiodarone-induced thyrotoxicosis (elevated levels of free thyroid hormone) can be sudden and require rapid assessment and treatment.¹⁶ Pharmacists must educate their patients about the symptoms of hyperthyroidism and instruct them to report them immediately if encountered.

 

PAUSE AND PONDER: How many of your patients take medications that might cause thyroid dysfunction? Why is it important to tell these patients that some of their medications might influence the thyroid gland?

 

PREVALENCE

As many as 20 million Americans are affected by thyroid disease. Clinicians diagnose hypothyroidism in nearly five of 100 Americans aged 12 years and older.²⁴ Thyroid disease affects men, women, and children. Women are disproportionately affected at a 10 to 15 times higher rate, and it’s estimated one in eight women will develop some form of thyroid disease in their lifetime.²⁴

 

HT is most often diagnosed between the ages of 40 to 60 years. Prevalence increases with age.⁸ Twenty percent of adults older than 75, most of them women, have insufficient levels of thyroid hormone.²⁴ The Colorado Thyroid Disease Prevalence Study, a cross-sectional study conducted more than 20 years ago, reported the prevalence of hypothyroid disease in symptomatic and asymptomatic adults at 9.5%.²⁵ In people not taking thyroid hormone, prevalence was 8.5% and 0.4% for subclinical and overt disease, respectively.¹⁰

 

Hyperthyroidism is much less common than hypothyroidism. Prevalence of hyperthyroidism in the U.S. is estimated at 1.3%. GD is the most common cause of hyperthyroidism followed by toxic nodular goiter. GD is estimated to affect 1% of the population, mainly women of childbearing age. Incidence increases with age, and it is observed more frequently in Caucasians compared to other races. Mild hyperthyroidism occurs at a higher rate in iodine deficient geographic areas.¹²

 

SYMPTOMS

Because thyroid hormones affect nearly every organ system in the body thyroid disease’s symptoms are wide ranging and numerous. Symptoms vary depending on the type of thyroid disease and patients may experience few or many symptoms.²⁶ Clinicians should routinely monitor patients for symptoms of thyroid disease, especially those at risk for thyroid disease including elderly women (See Table 2).²⁷

 

Table 2. Thyroid Disease’s Common Symptoms
	Hypothyroidism	Hyperthyroidism
Whole body	Fatigue, lethargy, cold sensitivity	Hunger, fatigue, weakness, sweating, increased appetite, heat intolerance, insomnia
Mood/behavioral	Depression, irritability, sluggish, brain fog	Nervousness, restlessness, hyperactivity, panic attacks
Cardiac	Bradycardia, elevated cholesterol	Tachycardia, palpitations
Weight	Weight gain	Weight loss
Hair, skin, nails	Hair loss, dry skin/hair, brittle nails	Hair loss, warm skin
Eyes/face	Periorbital edema, puffy face	Proptosis (abnormal protrusion of eyes)
Gastrointestinal	Constipation	Frequent bowel movements
Menstruation/fertility	Heavy or irregular menstrual periods, fertility problems	Amenorrhea, lighter or irregular menstrual periods, fertility problems
Musculoskeletal	Joint/muscle pain	Osteoporosis
Thyroid presentation	May be enlarged	May be enlarged

 

Weight gain is a common and often first symptom of hypothyroidism. Up to 82% of women with HT have excess body weight and a third suffer from obesity.²⁸ Despite achieving euthyroidism (normal thyroid function) with levothyroxine treatment, many women continue to struggle to lose weight. Caloric reducing diets are often unsuccessful and excess body weight increases risk for comorbidities.²⁹

 

Food sensitivity and the effects of elimination diets on autoimmune disease have gained interest. An interventional/observational study evaluated the effect of an elimination diet in obese women diagnosed with HT. The researchers observed that women eliminating sensitive foods (foods that may cause an IgG antibody reaction) in addition to caloric reduction had a greater decrease in body mass index (BMI) when compared to women only reducing caloric intake.³⁰ Improvement in thyroid function laboratory parameters was also observed in the group eliminating sensitive foods.³¹

 

LABS TO ASSESS THYROID FUNCTION

Thyroid function is assessed mainly through readily available laboratory blood tests. Results of basic thyroid function laboratory tests largely differentiate and diagnose thyroid disease (See Table 3).

 

Table 3. Thyroid Function Tests in Hypothyroidism and Hyperthyroidism³²

	TSH (Thyrotropin)	FT4 (Thyroxine)	T3
Lab reference range*	0.5-4.8 mIU/L	0.7-1.8 ng/dL	80-220 ng/dL
Hypothyroidism
Primary, untreated	High	Low	Low or normal
Secondary to pituitary disease	Low or Normal	Low	Low or normal
Hyperthyroidism
Untreated	Low	High	High
T3 toxicosis	Low	Normal	High

*Reference ranges may vary among laboratories.

 

TSH is the best measurement to assess thyroid function. A normal TSH essentially rules out thyroid disease, except in the less common cases of disease affecting the hypothalamus or pituitary gland. The American Thyroid Association (ATA) recommends routine screening of TSH in adults beginning at age 35 and repeating the test every five years.²⁷

 

T4 is the primary thyroid hormone circulating in the blood. T4 is found in the body in two forms: free T4 and bound T4. More than 99% of T4 is bound. Because T4 is converted into T3, free T4 (FT4) is the more important hormone to measure. Any changes show up in T4 first; therefore, FT4 reflects thyroid gland function more accurately.³³ Assessment of T3 is primarily used to diagnose and manage hyperthyroidism. It is rarely assessed in hypothyroidism since it’s the last test to become abnormal.³⁴

 

Patients with thyroid autoimmunity disease develop thyroid autoantibodies. Measurement of autoantibodies may help diagnosis, but clinicians need not monitor them routinely for disease management. Physicians typically order TSH with reflex to FT4 to assess thyroid function in disease management. Reflex testing allows the laboratory to automatically add the FT4 test to the blood sample based on an abnormal TSH result.³⁵

 

Clinicians sometime use radioactive iodine uptake (a non-blood test) to assess thyroid function. Because iodine is a necessary component of thyroid hormone, administering radioactive iodine and calculating its uptake by the thyroid can determine if the gland is functioning properly. Very high uptake is associated with hyperthyroidism while low iodine uptake indicates hypothyroidism.³⁴

 

TREATMENT APPROACHES

Levothyroxine

Levothyroxine sodium tablets (Synthroid and many generics) are synthetic T4 and indicated as replacement therapy in all hypothyroidism, regardless of the cause. Thyroid replacement hormone has a narrow therapeutic index and prescribers must individualize each patient’s levothyroxine dose. It is available in 12 different strengths, making it possible for prescribers to titrate doses carefully and avoid under- or over-treatment. Tablets are color-coded and are available from many manufacturers. (See Table 4.)

 

Table 4. Various Strengths and Colors of Levothyroxine Tablets

Strength	Color
25 mcg	Orange
50 mcg	White
75 mcg	Violet
88 mcg	Mint green
100 mcg	Yellow
112 mcg	Rose
125 mcg	Brown
137 mcg	Deep blue
150 mcg	Light blue
175 mcg	Lilac
200 mcg	Pink
300 mcg	Green

 

Variability in levothyroxine absorption may exist across manufacturers. A cohort study in the Netherlands evaluated a forced switch of levothyroxine brand. The researchers concluded that a dose-equivalent levothyroxine brand switch might necessitate a dose adjustment.³⁶ The ATA recommends using a consistent manufacturer. If a brand switch is made, the pharmacy team must inform prescribers; it may necessitate a dose adjustment.³⁷

 

Sidebar: Tech Tasks for Thyroid Medications

 

• Inform patients about the importance of using a consistent brand of levothyroxine.
• Note brand of levothyroxine on each patient’s profile.
• Review levothyroxine shipments when restocking to assure consistent brand use.
• Tag all bags and inform the patient if a brand switch is made.

 

Peak therapeutic effect of levothyroxine is seen in four to six weeks. Prescribers often start levothyroxine at low doses and titrate in small increments of 12.5 to 25 mcg every four to six weeks based on TSH testing until achieving euthyroidism.³⁸ Average full replacement dose is 1.6 mcg/kg/day. Current ATA guidelines recommend adjusting the levothyroxine dose to resolve symptoms of hypothyroidism and to keep the TSH level within the range of 0.4 to 4 mIU/L.²⁹ Clinicians should assess thyroid function in patients on stable doses of levothyroxine every six to 12 months and within six to eight weeks of any dose change. Ongoing assessment helps avoid under- or over-replacement.³⁸

 

Adverse reactions associated with levothyroxine therapy are primarily those of hyperthyroidism and include the following³⁷:

• Anxiety
• Diarrhea
• Fatigue
• Hair loss
• Heat intolerance, excessive sweating
• Increased appetite
• Increased heart rate
• Muscle weakness
• Nervousness
• Palpitations
• Weight loss

 

Over-replacement with levothyroxine can lead to serious consequences and can put elderly patients at risk for cardiac arrhythmias, especially atrial fibrillation.¹⁰ Complications of over-replacement include

• Accelerated bone loss
• Increased cardiac contractility
• Increased cardiac wall thickness
• Increased heart rate
• Osteoporosis
• Reduction in bone mineral density

 

Medications, supplements, food, coffee, and even orange juice can decrease levothyroxine’s absorption.¹⁰ Levothyroxine is taken with water one hour before breakfast and any other prescription medications. Calcium, iron, antacids, cholestyramine, and sucralfate can inhibit its absorption and must be separated by at least four hours.³⁷ Individuals with celiac disease or gastric bypass surgery may absorb medication inadequately.^40,41

 

Bedtime dosing of levothyroxine offers an alternative to morning dosing. Randomized controlled trials have found patients taking the medication in the evening had improved thyroid hormone status control.^38,42 Patients struggling with morning dosing may find evening dosing easier. The ATA recommends that if levothyroxine is taken at bedtime that it be separated by three hours from the evening meal.⁴³

 

Because levothyroxine is usually administered for life, dose adjustment is often necessary to optimize therapy throughout a patient’s lifetime.⁴⁴ Situations that necessitate possible dose adjustment of levothyroxine include

• Aging (age older than 65)
• Diagnosis of new medical conditions
• Pregnancy
• Start of new medications
• Weight changes

 

The Colorado Thyroid Disease Prevalence study assessed thyroid function, symptoms, and corresponding lipid levels in more than 25,000 participants. Among patients taking thyroid medication, only 60% were within the normal range of TSH. Modest TSH elevations corresponded to changes in lipid levels that may affect cardiovascular health.²⁵ Optimization of levothyroxine therapy requires that the healthcare team recognize the need for dose adjustments throughout a patient’s life.

 

PAUSE AND PONDER: Among your patients being treated for hypothyroidism, how many also take calcium supplements? How many of these patients know to separate them from levothyroxine by four hours?

 

Liothyronine

Liothyronine (Cytomel) is synthetic T3. It is not recommended, either alone or in combination with levothyroxine, as first line treatment for hypothyroidism. Combination therapy hopes to mimic thyroid hormone physiology more closely; however, current guidelines do not suggest routine use of this approach.¹⁰ A 2016 randomized, double blind, crossover study evaluated combination therapy in 32 patients and found no clear clinical benefit and observed increased heart rate in patients receiving it.⁴⁵A trial, however, may be indicated in a small group of patients who remain symptomatic despite adequate levothyroxine monotherapy.⁴⁶

 

Iodine

Patients with iodine deficient hypothyroidism are treated with iodine supplements to correct the deficiency while levothyroxine is used to achieve euthyroidism. When the iodine level has been restored and goiter size has decreased, levothyroxine may be interrupted. Prescribers should reassess thyroid function in four to six weeks.¹¹

 

Consumption of too much iodine can have a negative impact on thyroid health. The safe upper limit of iodine for adults is 1.1 mg/day.⁶³ Iodine toxicity may lead to thyroiditis, hypothyroidism, hyperthyroidism, and thyroid papillary cancer.⁴⁷ Pharmacists should be aware that drug interactions with potassium iodine exist. It can interact with antithyroid drugs and when potassium iodide is taken with ACE inhibitors or potassium sparing diuretics, serum potassium can increase.¹³

 

Selenium

Selenium is an important micronutrient in the diet and increases active thyroid hormone production. The RDA for selenium is 55 mcg/day. Selenium supplements are used to treat or prevent selenium deficiency. Doses exceeding 400 mcg/day can be toxic. Signs of toxicity include brittle hair and nails, diarrhea, irritability, and nausea. Extremely high intakes of selenium can cause severe problems, including difficulty breathing, tremors, kidney failure, heart attacks, and heart failure. Most people consume adequate selenium through the diet, which is preferred. Consuming two Brazil nuts daily can provide adequate selenium intake; each nut contains 68 to 91 mcg of selenium, so people should not consume too many. Selenium is also found in oysters, tuna, whole-wheat bread, sunflower seeds, meat, mushrooms, and rye.⁴⁸

 

Subclinical Hypothyroid Disease

Subclinical hypothyroidism is a common condition occurring in about 15% of older women and 10% of older men.² It is a persistent condition in which TSH levels are elevated but free T4 levels remain normal. Treating subclinical hypothyroidism with levothyroxine results in an improved quality of life for many while others show no benefit and continue to complain of symptoms despite treatment.

 

The decision to treat subclinical hypothyroidism is being reevaluated after a large European study found no clear benefit with treatment.³ Published in the New England Journal of Medicine in 2017, this double-blind, randomized, placebo-controlled, parallel-group trial concluded levothyroxine provided no apparent benefits in older people with subclinical hypothyroidism.⁴⁹ Investigators are conducting more research to evaluate the effect of discontinuing levothyroxine in subclinical hypothyroidism.⁵⁰ They hope to determine if discontinuing levothyroxine in patients with subclinical hypothyroidism is safe or will reduce quality of life.

 

For now, prescribers should follow current clinical practice guidelines, which state that they should tailor the decision to treat subclinical hypothyroidism to the individual patient when the serum TSH is less than 10 mIU/L. Prescribers should consider the presence of symptoms and how likely the patient will progress to overt hypothyroidism when making the decision to treat.²⁴

 

Antithyroid Drugs

The treatment goal for hyperthyroid disease is to lower excessive thyroid hormone levels and achieve euthyroidism. The two antithyroid drugs (ATD) available in the U.S. for the treatment of hyperthyroidism are methimazole (Tapazole) and propylthiouracil (PTU). Hepatotoxicity has been reported with both medications but methimazole has been associated with far fewer cases. Therefore, methimazole is used as first line therapy, except in pregnancy.⁵¹

 

ATDs inhibit T4 and T3 synthesis by blocking oxidation of iodine in the thyroid gland. PTU also partially blocks peripheral conversion of T4 to T3. Beta-blockers can provide symptomatic relief in patients with hyperthyroidism.

 

Methimazole is available in 5 mg and 10 mg tablets. The starting dose is 5 mg to 20 mg orally every eight hours. Prescribers must titrate the dose over time to the lowest dose needed to maintain euthyroidism. Maintenance doses range from 5 mg to 30 mg/day administered once daily. Once euthyroidism is achieved, patients usually continue the ATD for another 12 to 18 months. The prescriber should check thyroid function four to six weeks after therapy initiation and then every two to three months once the patient is euthyroid.¹²

 

PTU’s labeling carries a boxed warning for acute liver failure, and it is reserved for use in those who cannot tolerate other treatments such as methimazole, radioactive iodine, or surgery.⁵² It is also recommended for use in the first trimester of pregnancy because birth defects have been associated with methimazole. PTU is available as a 50 mg tablet. The initial starting dose is 50 mg to 150 mg orally every eight hours and the maintenance dose is usually 50 mg every 8 to 12 hours.⁵³

 

Minor side effects occur in about 5% of patients receiving an ATD. Side effects include⁵³

• Agranulocytosis (severe drop in white blood cells)
• Arthralgia
• Gastrointestinal distress
• Hepatotoxicity
• Pruritus
• Vasculitis (dangerous inflammation of blood vessels)

 

Serious side effects are less common at lower doses; patients should be maintained at the lowest possible dose needed to achieve euthyroidism. Although rare, hepatotoxicity and agranulocytosis can be life threatening. Pharmacists should educate patients to report signs of agranulocytosis, such as sudden fever, sore throat, or chills, to their prescribers immediately. Prescribers should obtain a baseline serum liver profile and white blood cell count before starting an ATD. Most side effects occur within the first 90 days of therapy. Vasculitis is more common with longer duration of therapy.

 

A drawback of ATD therapy is the high relapse rate. A longitudinal cohort study concluded that patients initially treated with an ATD had about a 50% relapse rate and 25% felt they had not fully recovered in six to 10 years.⁵⁴

 

Recent studies have shown that longer treatment time with an ATD can achieve higher remission rates. A randomized, parallel-group study compared relapse rates in patients receiving longer-term versus conventional-length methimazole therapy in GD. The authors concluded that low-dose methimazole treatment for 60 to 120 months was safe and effective and had a higher remission rate compared to conventional treatment for 18 to 24 months.⁵⁵

 

Long-term methimazole therapy was also evaluated in juvenile GD in a randomized parallel trial. Patients receiving short-term methimazole therapy were almost three times more likely to relapse than those on long-term therapy. The researchers found long-term methimazole treatment of 96 to 120 months to be safe and effective with a significantly higher four-year cure rate.⁵⁶

 

Teprotumumab

The FDA’s approval of teprotumumab (TEPEZZA) in January 2020 was the most significant advance in treating thyroid eye disease in decades. Teprotumumab binds to IGF-1R and blocks its activation and signaling. It was shown to improve the course of thyroid eye disease in patients in two separate clinical trials, leading to this monoclonal antibody’s approval.^23,57 Proptosis and diplopia improved, as did eye pain, redness and swelling, and quality of life. Serious adverse events were uncommon. The most common adverse reactions observed were

• alopecia
• altered sense of taste
• diarrhea
• dry skin
• fatigue
• headache
• hearing loss
• hyperglycemia
• muscle spasm
• nausea

 

The FDA approved teprotumumab to be given as an infusion every three weeks for a total of eight doses. Patients completing the course of therapy showed significant improvement in symptoms associated with thyroid eye disease. Infusion reactions are reported in about 4% of patients. Dose is based on weight. The first dose is 10 mg/kg, and then the dose is increased to 20 mg/kg for the remaining seven infusions. Teprotumumab is contraindicated in pregnancy. Women of childbearing age must be counseled on pregnancy prevention during treatment and for six months following the last dose.⁵⁸

 

PAUSE AND PONDER: Which patients with thyroid disease in your practice might benefit from teprotumumab? What is important to tell them about this new biologic?

 

Surgery

Thyroidectomy is not used as a first line approach for treating hyperthyroidism. It is reserved for patients who refuse radioactive iodine after relapsing on an ATD, patients who cannot tolerate an ATD, or patients with very large goiter, multinodular goiter, or toxic adenoma. Thyroidectomy destroys the thyroid gland and if indicated, patients require lifelong levothyroxine therapy.

 

Radioactive Iodine

In the U.S., radioactive iodine is the most common treatment for hyperthyroidism. Radioiodine therapy, like surgery, destroys the thyroid gland requiring patients to be on lifelong levothyroxine therapy.

 

In the last 20 years, radioiodine has been used less frequently.¹⁹ Many patients report a lower quality of life after receiving radioactive iodine than patients receiving ATD or surgical treatment.⁵⁹ A randomized parallel group trial found that long-term methimazole, when compared to radioiodine, was safe, effective, and not inferior to radioiodine further supporting the use of ATD over radioiodine.⁶⁰

 

Pregnancy

Undiagnosed or inadequately treated hypothyroidism during pregnancy can lead to miscarriage, preterm delivery, or developmental disorders in children. Levothyroxine is safe in pregnancy, but pregnant patients may require a 30% increase in levothyroxine dose to maintain euthyroidism. During pregnancy, attending healthcare providers should titrate levothyroxine doses against TSH, which has trimester-specific ranges. Postpartum TSH levels are similar to preconception levels, so the dose of levothyroxine should return to the preconception dose following delivery.⁶¹

 

Iodine is a critical mineral for proper fetal development and iodine needs increase by at least 50% in pregnancy and lactation. Pregnant women should receive a prenatal vitamin containing 150 mcg of iodine during pregnancy and lactation. Unfortunately, prenatal vitamins contain variable and inconsistent amounts of iodine. Close to 40% of marketed prenatal vitamins in the U.S. contain no iodine and when measured, the actual iodine content varied between 33 and 610 mcg.¹¹ Healthcare practitioners must be vigilant in assuring that iodine requirements are met during pregnancy and lactation when iodine requirements increase. The ATA recommends that women receive 150 mcg of supplemental iodine daily during pregnancy and lactation and that all prenatal vitamin/mineral preparations contain 150 mcg of iodine.¹¹

 

Hyperthyroidism in pregnancy requires special consideration. Care givers must stabilize women undergoing treatment for GD who intend to become pregnant prior to conception. Prescribers should advise women to delay attempts at conception until they achieve a stable euthyroid state, whenever possible.⁶² Additionally they should treat hyperthyroidism during pregnancy with the lowest possible dose of PTU because methimazole has been associated with cases of congenital malformation.

 

The majority of patients with thyroid eye disease are women of childbearing age. Physicians must explain treatment limitations to patients who are contemplating pregnancy. Teprotumumab is contraindicated in pregnancy. Caregivers must provide contraceptive counseling to women of childbearing age with thyroid eye disease treated with teprotumumab during treatment and for the six months following therapy.²³

 

Pharmacy Team’s Role

The pharmacy team can have a positive impact on the successful management of patients with thyroid disease by educating and screening patients regarding

• Adverse effects associated with their thyroid medications
• Importance of medication adherence
• Laboratory assessment of thyroid function
• Screening for drug interactions
• Signs and symptoms of hyperthyroidism and hypothyroidism

 

CONCLUSION

Thyroid disease affects millions in the U.S. and most cases are well controlled with pharmacological management. Adherence to thyroid disease medications is important. A knowledgeable pharmacy team can promote good practices and provide patient education, having a positive impact on patient care. Proper management allows most patients to have an excellent prognosis and quality of life.

 

With your newly gained knowledge, take another look at the Mona Lisa. Did Leonardo da Vinci, a man before his time, notice a thyroid disorder that he captured in his famous painting and did it intentionally contribute to her enigmatic smile?

 

 

 

Download CE Activity

INTRODUCTION

Let’s start this continuing education (CE) course with a story. A 13-year-old adolescent, Emily, had asthma exacerbations that were impacting her life. In addition to sitting out at her soccer games, she was having difficulty waking for school because her asthma exacerbations kept her up a few nights a week. Her physician prescribed a budesonide/formoterol (Symbicort) prescription for maintenance and reliever. When she and her mom went to pick up the prescription, their pharmacist told them this prescription was “inappropriate” and “dangerous” at the pick-up counter. This pharmacist likely frightened the patient and her mother. The patient would have been rightfully hesitant to take the prescription as the physician prescribed.

 

Although the guidelines did not recommend using this combination for reliever and maintenance before 2020, the pharmacist was mistaken. This pharmacist didn’t know about new NHLBI guidelines for SMART therapy. This continuing education activity will explore a recent change to the asthma guidelines that helps aspiring soccer players like our Emily score a goal with their asthma. Staying up to date on guidelines is the only way pharmacists will keep their place as trusted healthcare professionals.

 

BACKGROUND

All pharmacy team members need to know about asthma because it is a common chronic disease in both children and adults. The Center for Disease Control (CDC) estimates that around 8% of the population has asthma. As a chronic disease affecting the airway and lungs, asthma is characterized by airway inflammation, bronchospasm, and mucus hypersecretion. These findings cause symptoms of difficulty breathing, wheezing, coughing, and chest tightness.¹ Asthma’s symptoms can range from mild to severe and they fluctuate. Symptom worsening is called an asthma attack, flare, or exacerbation.²

 

Asthma is often diagnosed in childhood but affects people of all ages. It is diagnosed more commonly in males during childhood, but its prevalence is equal in males and females by adulthood.¹ Asthma seems to have a hereditary component, although many genes probably contribute to asthma.³ Family history and the presence of eczema are both risk factors for asthma.¹ Other risk factors include exposure to environmental tobacco smoke, air pollutants, or allergens, such as pollen, dust, or workplace chemicals (see the SIDEBAR for information about household pests).¹ Risk factors for asthma are often present in childhood. For example, exposure to cigarette smoke in the womb increases the probability infants will develop asthma. Young children with allergies or who have respiratory infections are also more likely to develop asthma.¹

 

Asthma Pathophysiology

The bronchial tree is the branched system of cartilaginous tubes responsible for conducting gas to alveoli, the small air sacs that allow gas exchange, in the lungs. The word “tree” is an apt description because the lungs look like an upside-down tree, where the trachea is the trunk, and the bronchioles are the smallest terminal twigs. The bronchioles are the smallest bronchi and they facilitate gas exchange with alveoli, the air sacs in the lungs that exchange gas with the blood.⁴ Each layer of the bronchi has a smaller diameter than the one it stems from and has more smooth muscle fibers, just like the branches of a tree.⁵ Asthma primarily affects airways including the smooth muscle of the bronchi, where inflammation decreases the airway’s size, in turn increasing the work it takes to breathe.³

 

In allergic asthma, an asthma exacerbation consists of an early phase and a late phase. IgE antibodies are responsible for the first phase.³ Environmental triggers cause plasma cells to release IgE antibodies, which bind to mast cells and basophils. Mast cells release cytokines, histamine, prostaglandins, and leukotrienes.³ Ultimately, smooth muscle contracts and the airway tightens, causing bronchoconstriction.⁶ Th2 lymphocytes sustain the inflammation by producing additional cytokines and maintaining the communication between cells.³ The late phase occurs over the next few hours as inflammatory cells localize to the lungs and cause bronchoconstriction and inflammation. The cells involved in this second phase include basophils, eosinophils, helper and memory T-cells, and neutrophils.³ These cells cause inflammation and further edema. Mucus worsens airway obstruction and difficulty breathing. Successful management of an asthma exacerbation requires recognition of both phases.

 

Hyperresponsiveness of the bronchi is another mechanism of asthma’s pathophysiology. Hyperresponsiveness is excessive bronchoconstriction after inhalation of or exposure to triggers.⁷ Triggers can include smoke, exercise, emotion, cold temperatures, humidity, animals with fur, infections, and non-steroidal anti-inflammatory drugs.^8-11 This mechanism of excessive inflammation involves histamine and increased free intracellular calcium that increases smooth muscle contractility.¹² Disease severity and therapeutic intervention are related to bronchial hyperresponsiveness.

 

 

Rodent and Cockroaches Sidebar^13-15

The prevalence of asthma is highest in developed countries, especially in urban areas. In urban areas, up to 1 in 4 children may have asthma. Urban areas increase the risk of exposure to cockroaches and rodents, increasing allergen sensitization in these areas, ultimately leading to asthma. Mouse Mus m 1, mouse urinary protein (MUP), rat N 1, and cockroach (Bla g 1 and Bla g 2) are the responsible allergen proteins. Tests have confirmed high levels of these proteins in houses, schools, and daycares in urban locations.

 

Multifamily homes, high population density, lower socioeconomic status, and poor physical condition of buildings are all settings that foster cockroach and rodent infestation. Sensitization to cockroaches and rodents is associated with wheezing and severe asthma morbidity. Most research done to date has been in children.

 

Like people, pests need food, water, and shelter to live. They prefer to live in dark and damp areas. Pest mitigation strategies can decrease the likelihood of exposure to rodent and cockroach proteins:

 

• Do not leave food containers open or dirty dishes out in the open.
• Do not leave pet food and water out overnight.
• Clean regularly. Pick up garbage, crumbs, and clean liquid spills.
• Use trash cans with lids, bags that resist breaking, and do not allow them to overflow.
• Check for plumbing leaks and moisture problems and fix any issues right away.
• Seal cracks and openings around doors, windows, and foundations.
• Use bait gel in cracks and traps rather than pesticides.

 

Structural changes occur in the airway due to chronic inflammation and airway muscle hyperreactivity. This is known as airway remodeling. An asthmatic bronchiole is narrower than a normal bronchiole. Increased swelling, chronic inflammation, and mucus buildup from persistent airflow obstruction cause the narrowing.³ The narrowing of the lumen disrupts the normal replication of epithelial cells, compromising the layer’s structure and function.¹⁶ The hyperresponsiveness of the bronchioles leads to hypertrophied smooth muscle, disrupting the basement membrane. Irreversible obstruction of airflow is a consequence of airway remodeling.¹² Effective treatment of asthma can prevent or delay airway remodeling.

 

ASTHMA DIAGNOSIS

The first step in diagnosing asthma is a focused medical history and physical examination. Symptoms consistent with asthma include episodes of cough, wheezing, difficulty breathing, and chest tightness. It is also notable if these symptoms worsen at night and awaken the patient, as they did for our patient Emily.¹⁷ The physical exam may show use of accessory muscles when breathing, sounds of wheezing during normal breathing, increased nasal secretion with mucosal swelling, or atopic dermatitis/eczema.¹⁷ Noting patient allergies or a family history of asthma helps establish a diagnosis.

 

Spirometry can be used to evaluate asthma and monitor disease severity; it can also be used to monitor response to therapy in patients aged 5 and older.  Of note, it is not common to find many five-year-olds who are capable of reliably performing the test.¹⁷ Spirometry measures the air a patient breathes in and out. Specifically, spirometry measures the forced expiratory volume in 1 second (FEV₁) and the forced vital capacity (FVC).¹⁸

• FEV₁: maximum amount of air a patient exhales in one second.
• FVC: maximum amount of air exhaled when blowing out as fast as possible

 

Comparing results against values normalized by age, height, weight, gender, and race is the only way to interpret them. An easy way to interpret results is based on the percent predicted; however, most pulmonologists now use z-scores to interpret spirometry.¹⁹ Physicians may have the patient repeat spirometry after taking a bronchodilator to evaluate for airway reversibility.

 

Clinicians also use spirometry to evaluate if current therapy is controlling asthma effectively. The results of patients’ spirometry tests while on treatment guides doctors to increase or decrease the dose of asthma medications.¹⁸

 

Airway hyperresponsiveness is measured using a methacholine test. The clinician uses spirometry to find the patient’s FEV₁. The patient then uses a nebulizer and inhales increasingly larger doses of methacholine. The physician takes the FEV₁ before and after each dose. The test is positive if the FEV₁ drops 20% or more from the baseline FEV₁. The test is negative if the maximum methacholine dose does not decrease the FEV₁ by at least 20%.²⁰ Regardless of asthma control and response to therapy, most people with asthma would have a positive methacholine challenge test.

 

The 2020 NHLBI guideline update includes the conditional recommendation to use fractional exhaled nitrous oxide (FeNO) as a test to diagnose asthma.²¹ Nitric oxide (NO) is a gas produced by cells involved in inflammation. The higher the NO level, the more inflammation in the body. This test is plausible to use as an adjunct for patients aged 5 and older whose asthma diagnosis is uncertain using history, clinical course, and spirometry. Our patient in this CE case would not be a candidate for a FeNO test, as her asthma diagnoses are apparent without one. One should also note that most commercial insurances no longer cover this test.

 

Asthma Severities

The NHLBI classifies asthma as intermittent, mild persistent, moderate persistent, or severe persistent. Asthma symptoms before treatment determine the classification, but the patient’s classification may change over time. Patients are diagnosed with the asthma classification in which their most severe symptom falls.¹⁷ As you look at these classifications, think about Emily and decide where her asthma would fall.

• Intermittent Asthma
  • Symptoms occur fewer than two days a week and do not interfere with normal activities
  • Nighttime symptoms occur fewer than two days a month
  • Lung function tests are normal when the patient is not having symptoms
• Mild Persistent
  • Symptoms occur more than two days a week, but not every day. Attacks interfere with daily activities
  • Nighttime symptoms occur three to four times a month
  • Lung function tests are normal when the patient is not having symptoms
• Moderate Persistent
  • Symptoms occur daily and interfere with daily activities
  • Nighttime symptoms occur more than once a week, but not daily
  • Lung function tests are abnormal
• Severe Persistent
  • Symptoms occur daily and severely limit daily activities
  • Nighttime symptoms occur multiple times weekly
  • Lung function tests are abnormal

 

The severity of asthma drives the treatment recommendations. Asthma classification can change over time. From our case, Emily likely has moderate persistent asthma. She is kept up a few times weekly by nighttime symptoms, interfering with her sleep. She also needs to sit out of soccer games and was having trouble in school due to her lack of sleep. Her symptoms limit her daily activities.

 

Pause and Ponder: How would asthma attacks occurring nightly affect a patient’s quality of life?

 

TREATMENT

 

With the revision to the guidelines in 2020, several things have changed, and pharmacy staff need to be aware of the changes.

 

Medications

People can manage asthma with appropriate medications. Table 1^22-26 provides additional detail on the mechanism of action, pharmacology, and adverse events associated with preferred medications used to treat asthma. Inhaled corticosteroids (ICS) are the cornerstone of asthma therapy, and this has not changed with the updated guidelines, although use of biologic agents to control asthma is more prominent.²³ ICS may be dosed once or twice daily but more often during symptomatic periods.²⁴ Beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate, and mometasone are all commonly used ICS.²² When dosed at equipotent doses, all corticosteroids are equally effective, but some individuals respond better to certain ICS than others.²⁴ The dose of ICS can be titrated for symptom relief and spirometry response, but the dose response is relatively flat after moderate doses.²⁵ A flat dose response is like continuing to eat when you are already full. When you are full, you likely have gotten all the calories you need from a meal, and now you are just increasing your chances of bellyache. Increasing the dose of ICS past moderate strengths does not continue to provide additional relief of asthma symptoms as before, and the risk of side effects increases. Some patients with severe asthma do escalate to high dose ICS.

 

Table 1. Preferred Medications for Asthma Therapy^22-26

 

Medication Class	Mechanism of Action	Pharmacology	Adverse events
ICS	Inhibit production and release of signals allowing extravasation of immune cells into the airway. Decrease inflammatory response and airway hyperresponsiveness	·       1-2 Weeks of treatment for full effect ·       Goal is high pulmonary affinity with low systemic absorption ·       MDI vs. DPI may affect absorption ·       Metabolism and active metabolites may contribute to systemic effects	Nasopharyngitis, headache, bronchitis, sinusitis, influenza, respiratory tract infection, back pain, toothache, abdominal pain, cough, oral candidiasis, rhinitis, and throat irritation
Inhaled SABA	Bind to beta-adrenergic receptors in the bronchiole. Ultimately leads to the relaxation of smooth muscle. The difference between short and long- acting agonists is the half-life.	·       Onset: Within minutes ·       Peak: 30 minutes ·       Bronchodilation: 4-6 hours	Tremor, nervousness and insomnia in children, nausea, fever, bronchospasm, vomiting, headache, pain, dizziness, cough, dry mouth, sweating, chills, dyspepsia
Inhaled LABA		·       Onset: 5-30 minutes ·       Peak: 15 minutes- 3 hours ·       Bronchodilation >12 hours	Adverse events are same as short acting, but less likely. LABAs are more B2 selective and lipophilic, concentrating their effects in the lungs
Inhaled SAMA	Antagonize acetylcholine at muscarinic (M3) receptors, leading to decreased bronchoconstriction, mucus secretion and edema	·       Onset: Within 15 minutes ·       Peak: 1-2 hours ·       Bronchodilation: 6-8 hours	Adverse events are related to systemic anticholinergic activity at all muscarinic receptors including urinary retention, dry mouth, headache, dizziness, sinusitis, dyspnea, back pain, cough
Inhaled LAMA		·       Onset: 30 minutes ·       Peak: 3-4 hours ·       Bronchodilation: 12 to >24 hours
B2: Beta-2 receptor, ICS: inhaled corticosteroids, DPI: dry powdered inhaler, LABA: long-acting beta agonist, LAMA: long-acting muscarinic antagonist, MDI: metered-dose inhaler, SABA: short-acting beta agonist, SAMA: short-acting muscarinic antagonist

 

Patients use oral systemic corticosteroids for severe exacerbations or if they have a history of severe exacerbations or difficult-to-control asthma.²¹ Oral corticosteroids have many unfavorable adverse events that need to be considered by prescribing physicians.²⁷ An increase in the release of cortisol from the adrenal glands through a negative feedback loop on the hypothalamus-pituitary-adrenal (HPA) axis causes many of these adverse effects.²⁷

Systemic corticosteroid adverse events differ by duration of therapy²⁷:

• Short term: hyperglycemia, leukocytosis, mood alteration, sodium and fluid retention, increased weight gain, nocturnal enuresis
• Long term: growth retardation, osteoporosis, skin thinning, impaired wound healing, bruising, cataracts, glaucoma, Cushingoid feature, increased weight gain, and immunosuppression

 

ICS have little systemic absorption and are preferred for asthma control over oral corticosteroids. Patients taking higher doses of ICS have increased risk of systemic absorption and adrenal suppression. It is important to titrate to the lowest effective dose of ICS to avoid systemic absorption and adverse events. Corticosteroids have a dose-response relationship to adverse events.²⁷ Clinicians must monitor for systemic side effects to determine the risk and benefit balance of both oral corticosteroids and ICS.

 

While corticosteroids treat the inflammatory component of asthma, additional medications are needed to address airway hyperresponsiveness and can be either short or long-acting medications. “Quick-relief” and “relief” medications are common ways to refer to short-acting medications.²² Short-acting beta-agonists (SABAs) and inhaled short-acting muscarinic antagonists (SAMAs) are the two classes of relief medications. Patients use SABAs and SAMAs when experiencing symptoms or before exposure to triggers.

 

SABAs are highly effective bronchodilators but have short durations of action.²² Typically, all patients with asthma are prescribed SABAs as a “relief” inhaler.²² Albuterol metered-dose inhalers (MDI) are the most used relief inhaler. Albuterol is dosed at one to two puffs every four to six hours as needed to control an asthma exacerbation.²⁸ SABA use is changing in clinical practice. Newer research shows that SABAs are more effective when followed by an ICS.²⁹ Even in patients with infrequent symptoms, a prescription for daily low-dose ICS reduces asthma symptoms and risk. Increased SABA use is associated with worse outcomes. A patient is at risk of severe asthma exacerbations and asthma mortality if they pick up three or more albuterol inhalers a year from the pharmacy, the equivalent of 1.6 puffs per day.²⁹

 

SAMAs can be used in place of SABAs but are less effective. SAMAs will be used if SABAs are not tolerated as relief therapy. Ipratropium is a commonly used SAMA. Emily, our patient in the CE case, does not have a SAMA prescription because she receives symptom relief when using albuterol. The APPENDIX describes the different types of inhalers and points that technicians can emphasize when patients pick up refills.

 

 

Long-acting medications include long-acting beta-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs). LABAs are never used alone in asthma therapy but are companions to inhaled corticosteroids (ICS).²² Patients should take these medications even when asthma symptoms are not present because they are maintenance therapy. All LABA medications have a boxed warning cautioning about the potential for severe asthma exacerbations. Some severe exacerbations, when using LABA monotherapy, have led to death.²² LABAs do not have the same association with severe exacerbations and death when used in a combination with ICS. Salmeterol and formoterol are the most frequently used LABAs.²² The two LABAs differ in their time of onset. Formoterol and salmeterol have an onset of 15 minutes and 45 minutes, respectively. Patients aged 6 and older can use tiotropium as an add-on LAMA in maintenance therapy.³⁰ Table 2^28,30-46 gives an overview of the current inhaled therapies available in the US to treat asthma. You will find details about Emily’s long-acting therapy in the section where SMART is explained.

 

 

Table 2. Asthma Inhalers ^28,30-46

Class	Drug	Brand	Dosage Forms
ICS	Beclomethasone dipropionate	QVAR Redihaler	MDI
	Budesonide	Pulmicort Flexhaler Generic	DPI Nebulizer
	Ciclesonide	Alvesco	MDI
	Fluticasone propionate	Flovent HFA Flovent Diskus Arnuity Ellipta Armon Air Digihaler	MDI DPI DPI DPI
	Mometasone	Asmanex HFA Asmanex	MDI DPI
SABA	Albuterol	ProAir Ventolin Proventil Generic	DPI, MDI MDI MDI DPI, MDI
	Levalbuterol	Xopenex HFA	MDI
LABA	Formoterol	Perforomist	Nebulizer
	Salmeterol	Serevent	DPI
SAMA	Ipratropium	Atrovent HFA Generic	MDI Nebulizer
LAMA	Tiotropium	Spiriva Respimat	DPI

 

 

Many patients require multiple medications for asthma management. Clinicians prescribe combination inhalers—inhalers that have two medications—to increase efficacy, patient adherence and ease of inhaler use. Patients experience less confusion about when and how to use their inhalers when using fewer products. Clinicians can assess patient adherence and correct use of medications when a patient is on combination products. With this information, clinicians can determine if the patient needs education or an increased medication dose. Table 3 ^47-52 shows the many combination products on the market.

 

Think back to our case. This patient's prescription was for budesonide/formoterol. This therapy is an ICS and LABA combined therapy. The patient previously used a fluticasone inhaler once daily and albuterol as a relief inhaler. This new therapy would give the patient only one inhaler to control her asthma, avoiding inhaler confusion.  Also, as patients cannot exactly “feel” the inhaled corticosteroid inhaler making a “difference,” but patients can always feel a change with SABA/LABA therapy—the combination inhalers help patients to experience a positive effect while taking chronic medications.

 

 

Table 3 Combination Products ^47-52

 

Budesonide/formoterol	Symbicort	MDI
Fluticasone/salmeterol	Advair	DPI, MDI
Fluticasone/vilanterol	Breo Ellipta	DPI
Mometasone/formoterol	Dulera	MDI
Budesonide/umeclidinium/ vilanterol	Trelegy Ellipta	MDI

 

 

The 2020 NHLBI Guidelines for Asthma Management list the following medications as alternatives to the preferred therapies: leukotriene receptor antagonists (LTRA), cromolyn (Intal), theophylline, and immunotherapies. The guidelines list nedocromil (Tilade) as an alternative therapy, although the FDA has discontinued this medication. ^21,53

 

LTRAs include montelukast and zafirlukast. These medications antagonize the effects of pro-inflammatory chemicals called leukotrienes. LTRAs work to decrease the inflammatory component of asthma.²² Montelukast is indicated in patients aged 1 and older, is only dosed once a day, and does not have many drug interactions.⁵⁴ Montelukast use is discouraged because of side effects and limited efficacy. Montelukast’s labeling includes a boxed warning because of potential neuropsychiatric adverse events.⁵⁴

 

Cromolyn is a nebulized solution approved for asthma prophylaxis. The approval is for patients aged 2 and older. It inhibits release of histamine and leukotrienes from mast cells.⁵⁵

 

Theophylline is an oral medication rarely used as maintenance therapy for asthma.  It has many side effects and requires titration via blood tests. It is a phosphodiesterase inhibitor and adenosine antagonist. Theophylline ultimately relaxes smooth muscles in the bronchial airway.²²

 

Immunotherapies are injectable monoclonal antibodies reserved for patients with severe and treatment-resistant asthma. Currently, omalizumab (Xolair) is the only biologic approved for asthma in patients as young as 4 years old. ²¹ The NHLBI 2020 guideline update does not contain specific recommendations for the use of biologics. The systematic reviews the panel examined to update the guidelines did not include the use of biologics. Anti-IgE (omalizumab), anti-IL5 (mepolizumab [Nucala], reslizumab [Cinqair]), anti IL5-R (benralizumab [Fasenra]), and anti-IL4 (dupilumab [Dupixent]) are other biologic treatments for asthma. Insurers typically require prescribers to document the patient’s allergen sensitization and phenotyping before approving immunotherapies. Patients will have to try other therapies and either be unresponsive or intolerant of them before trying biologics. Specialist supervision is needed.²²

 

Step Therapy Rationale

 

The NHLBI Guidelines recommend a stepwise approach to the treatment of asthma. The recommendation guides initial asthma treatment based on the asthma severity and subsequent therapy if symptoms persist despite changes in asthma therapy.²¹ Table 4 represents a combination of the stepwise therapy recommendations across all age groups in the NHLBI Guidelines.²¹ For simplicity, the figure only shows the preferred medication recommendations. The full step therapy recommendations can be found in the full version of the NHLBI 2020 Update to the Asthma Management Guidelines.

Table 4. Stepwise Approach to the Preferred Treatment of the Management of Asthma ²¹

 

Intermittent Asthma	Management of Persistent Asthma
Step 1	Step 2	Step 3	Step 4	Step 5	Step 6
Individuals Ages 0-4 years
PRN SABA Short daily course of ICS at the start of respiratory tract infection	Daily low-dose ICS       PRN SABA	Daily medium-dose ICS     PRN SABA	Daily medium dose ICS-LABA   PRN SABA	Daily high-dose ICS-LABA     PRN SABA	Daily high-dose ICS-LABA + oral systemic corticosteroid   PRN SABA
Individuals Ages 5-11 years
SABA	Daily low-dose ICS       PRN SABA	Daily and PRN combination low-dose ICS-formoterol	Daily and PRN combination	Daily high dose ICS-LABA     PRN SABA	Daily high-dose ICS-LABA + oral systemic corticosteroid   PRN SABA
Individuals Ages 12+
SABA	Daily low-dose ICS and PRN SABA or PRN concomitant ICS & SABA	Daily and PRN combination low-dose ICS-formoterol	Daily and PRN combination medium-dose ICS-formoterol	Daily high dose ICS-LABA       PRN SABA	Daily high-dose ICS-LABA + oral systemic corticosteroid     PRN SABA

 

In Step 1—which addressed patients with intermittent asthma—patients only use a reliever inhaler to control intermittent asthma symptoms, meaning the patients will only use an inhaler when experiencing symptoms or for pre-treatment before exercise. A clinician would initiate ICS therapy in a patient with mild asthma on Step 2.¹⁷ A patient with moderate asthma would start therapy on Step 3 or Step 4.¹⁷ A patient with severe asthma would start therapy on Step 5 or Step 6.¹⁷

 

Once treatment has started, a clinician should reassess the patient every two to six weeks to ensure control of asthma symptoms.²¹ If symptoms persist and asthma is uncontrolled, this would be an appropriate time to step-up therapy. Questioning patients about how frequently they use their reliever inhalers, or how many times they forgot to take their inhaler in the past week may help guide clinicians.¹⁷ More frequent use of the SABA, including using a reliever inhaler more than two days a week, would favor stepping up therapy. Appropriate use of asthma inhalers is critical to achieving control. Adherence to the regimen and proper technique are required to determine if the patient is using the medication correctly.²¹ Pharmacists can play an integral role in educating patients in proper inhaler technique.

 

Objective measures, like spirometry, can also be used to assess control. Improvements in spirometry readings indicate better control of a patient’s asthma.²¹ Increased healthcare utilization, like emergency room visits for an exacerbation, is another way to determine if a patient’s asthma is under control.¹⁷ An increase in patients’ healthcare utilization suggests poorly controlled asthma. Mitigating the risk of severe exacerbations is another goal of achieving good asthma control.¹⁷ Any patient on step 3 or higher should consult with an asthma specialist for treatment.²¹

 

If a patient has well-controlled asthma after three consecutive months on a medication, the patient also may step down on therapy.²¹ A patient would always only go down one step of treatment. A clinician would schedule follow-up in the same two-to-six-week timeframe to ensure a patient still has asthma control.¹⁷ The benefit of stepping down therapy is to lower the patient’s systemic ICS and LABA dose exposure, decreasing the risk of potential adverse events.

 

 

2020 NHLBI Asthma Management Guideline Updates

The 2020 NHLBI Guideline update focused on six select topics: intermittent ICS (e.g. SMART), LAMAs, indoor allergen mitigation, immunotherapy in the treatment of allergic asthma, FeNO testing, and bronchial thermoplasty (BT). A major update to the guideline that is changing clinical practice is SMART.

 

Time to be SMART

The 2020 NHLBI Asthma Management Guidelines recommend SMART in patients with moderate persistent asthma ages 4 and older. Keeping a patient's current regimen would be appropriate if asthma symptoms are well controlled. SMART employs a single ICS+formoterol combination inhaler product dosed daily and as needed for asthma exacerbations. This is a significant change, and all pharmacy staff need to be aware of it! SMART medications are FDA-approved in patients 12 and older. SMART is recommended off label in children aged 4 through 11.

 

Before the 2020 update, patients with moderate persistent asthma would be on Step 3 or Step 4 therapy. Therapy consisted of a daily ICS inhaler for maintenance and a SABA inhaler for relief—two separate inhalers. If a patient was uncontrolled on ICS, a physician added a LABA to the regimen. SMART potentially transitions patients from three inhalers to one inhaler. An ICS+LABA combination has never been a reliever option before; the only option was SABA. The drastic change in recommendations is why the pharmacist in the CE case, unaware of this change, was hesitant to fill the prescription. It is an extreme change in therapy and based on outdated information, and he was understandably uncomfortable.

 

It would be reasonable to switch patients who are uncontrolled on their current regimens or have had an exacerbation in the past year.²¹ It is also reasonable to discuss with patients or families who want to streamline their treatment regimens or those with difficulty adhering to their current regimens. Patients with uncontrolled moderate asthma should switch to SMART on the same treatment step they are currently on before moving up. For example, Emily in the CE case was on Step 4 of the 2007 guidelines, a medium-dose ICS and a LABA.¹⁷ After being transferred to SMART, her regimen includes a medium-dose ICS-formoterol. This is Step 4 of therapy in the 2020 guidelines.

 

Along with an ICS, formoterol, a LABA, is being used as the reliever component of the regimen. Using formoterol is entirely different than our previous approaches where SABAs and SAMAs were the reliever medications. Formoterol’s onset is two to three minutes.⁵⁶ Its duration of action is up to 12 hours, creating quick and durable smooth muscle relaxation.⁵⁶ Formoterol is also an ideal drug because patients can use it more than twice daily. The maximum dosage of formoterol varies by age. Each inhalation of SMART will deliver 4.5 mcg of formoterol. Patients aged 4 to 11 can use eight puffs of formoterol daily (36 mcg).²¹ Patients aged 12 and older can use twelve puffs of their inhaler per day (54 mcg).²¹

 

The two ICS currently used in SMART inhalers are budesonide and mometasone.⁵⁷ A patient using a SMART inhaler as needed will also receive the long-term anti-inflammatory effects of an ICS with each use. SMART therapy aims to provide enough long-acting preventive medicine when symptoms occur to prevent them from recurring.⁵⁷

 

This treatment will be prescribed as one to two puffs once or twice daily for maintenance with one to two puffs as needed every five to 10 minutes for asthma symptoms. Age, asthma severity, and ICS dose in the inhaler determine the dosage and frequency a clinician prescribes.²¹ Pharmacists should ensure the maximum puffs on a patient’s prescription do not exceed the limit for their age.

 

SMART reduces asthma exacerbations and decreases healthcare utilization while increasing quality of life and asthma control.²¹ SMART therapy also decreases patients’ systemic corticosteroid use. Patients who decrease their use of oral corticosteroids and maintain lower doses of ICS reduce the risk of corticosteroid-associated adverse events.⁵⁷

 

SMART may make asthma treatment easier for patients and families. Patients appreciate this one inhaler approach with a single prescription to refill and pickup.⁵⁷ Having a single inhaler decreases confusion about which inhaler is responsible for maintenance and reliever. It also ensures the patients always have the correct inhaler in their possession. SMART may be especially beneficial for patients who regularly skip their maintenance inhaler when they do not have symptoms.⁵⁷ These patients rely on their reliever inhalers. With SMART, if patients only take their reliever inhaler, they still receive anti-inflammatory medication.

 

Costs, insurance formulary considerations, and intolerance are all reasons SMART may not be appropriate for some patients.²¹ Patients who overuse their SABA reliever inhalers may not be good candidates for SMART. Some patients use their reliever inhalers when they are anxious or feel short of breath, even when this is not asthma related.⁵⁷ These patients are at risk of receiving ICS doses that are too high. Patients who use ICS-salmeterol as their maintenance should not use it as SMART.²¹ Patients using both inhalers will expose themselves to higher and potentially dangerous LABA & ICS doses.

 

Pharmacists are responsible for reminding patients to use only their maximum daily puffs and to contact a physician if their asthma symptoms require them to exceed this maximum. The pharmacist should also consider the supply a patient will need using the medication for both maintenance and relief doses. Patients may need to pick up multiple inhalers monthly for adequate supply.²¹

 

Pharmacy technicians will prevent errors if they can recognize SMART. These prescriptions will contain directions for daily use and as-needed use in the same inhaler. An example prescription is budesonide/formoterol 80/4.5, inhale 2 puffs twice daily and 1-2 puffs every 4 hours as needed for asthma exacerbations (maximum 12 puffs daily). Current evidence only recommends formoterol as the LABA in SMART. Knowing this, a technician can be on the lookout for the look-alike sound-alike medication salmeterol in combination inhalers which are not safe to use for SMART. A patient on SMART therapy will likely need all other prescriptions for asthma therapy put on hold. Let’s emphasize this point: Patients with automatic refills of a SABA or other maintenance medication will be at risk of over-treatment if they continue to take their old inhalers with SMART. If a patient with a SMART prescription comes into the pharmacy, it is important for the technician to recognize this to help prevent medication errors.

 

Pause and ponder: Who makes the ideal candidate for SMART therapy?

 

Additional Guideline Updates

Intermittent ICS²¹

The NHLBI organized the recommendations for the use of intermittent ICS by age. This update includes SMART.

 

The guidelines recommend that from birth to age 4, children with recurrent wheezing related to respiratory tract infections (RTI), not currently on asthma therapy and with no symptoms between infections should use a seven-to-ten-day course of daily ICS when the RTI begins.²¹ It recommends combining ICS with as-needed quick-relief SABA therapy. This recommendation aims to decrease exacerbations, systemic corticosteroid use, and healthcare utilization.²¹ Healthcare utilization declines when caregivers have clear instructions for initiating ICS.

 

Individuals aged 4 to 12 with mild to moderate persistent asthma who are currently taking daily ICS should not increase their regular daily ICS dose for short periods.²¹

 

Individuals aged 12 and older with mild persistent asthma have two preferred treatments recommended as Step 2 of therapy²¹: either a daily low-dose ICS and as-needed SABA or an as-needed SABA and ICS delivered concomitantly, one after the other.²¹ SMART therapy is the preferred treatment in patients with moderate to severe asthma in patients 4 and older.²¹

 

LAMAs

The 2020 NHLBI guideline update changed the recommendation for LAMA use in patients 12 years and older with asthma not controlled by ICS therapy. The next appropriate step is to add a LABA to ICS rather than a LAMA, unless the patient is unable to tolerate, has a contraindication, or has an adherence barrier to a LABA.²¹ A prescriber may still add a LAMA onto the ICS+LABA combination for improved symptom control and increased quality of life.²¹ A patient on ICS+LABA and LAMA will require the use of multiple inhalers.

 

Indoor Allergen Mitigation

Some patients have an identified allergen component of their asthma. Patients may use mitigation strategies like air purifiers, impermeable pillows, mattress covers, and HEPA filters to reduce their risk of allergen exposure.²¹ The 2020 NHLBI guideline update recommends patients use multiple mitigation strategies, as one strategy alone likely will not improve outcomes.²¹ The guideline recommends integrated pest management in patients' homes who are allergic and exposed to rodents and cockroaches.²¹ If an individual does not have an allergy to indoor substances, the 2020 Update does not recommend home mitigation strategies.²¹

 

Immunotherapy in the Treatment of Allergic Asthma

Immunotherapy includes subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT). The 2020 NHLBI guideline update recommends SCIT as an adjunct treatment in patients with demonstrated sensitization to allergens, but not when patients are experiencing asthma symptoms or have severe asthma.²¹

 

FeNO Testing

The 2020 NHLBI guideline update recommends FeNO measurement in patients older than 4 years with an uncertain asthma diagnosis after a medical examination, complete history, and spirometry testing.²¹

 

Bronchial Thermoplasty

BT is a procedure that removes muscle tissue from the airway using heat. The benefits in this procedure are small, the risks are moderate, and long-term outcomes are uncertain.²¹ The 2020 NHLBI guideline update conditionally recommends against this procedure.²¹ Patients who may consider BT must have a risk-benefits conversation with their provider.

 

Conclusion

The update to the 2020 NHLBI Asthma Management Guidelines offers new guidance to clinicians treating patients with asthma. Patients need to go to the pharmacy and pick up their evidence-based treatment without unnecessary intervention—or incorrect and possibly frightening information—from the pharmacist. Pharmacists should expect to see prescriptions of ICS-formoterol written for SMART. The patient case in this CE is an avoidable situation. Staying up to date with the current guidelines is a pharmacists’ responsibility. Technicians should work with patients and pharmacists to put outdated medication prescriptions on hold to avoid further medication errors.

 

Pharmacy Technician Sidebar: Education on DPI/ MDI/ Nebulizer

 

Proper inhaler technique is an essential aspect of asthma control. It may seem like a silly statement, but there are different kinds of inhalers and devices. Each inhaler requires patients to use specific inhalation techniques that deliver medications effectively. Some patients may have multiple inhalers, complicating their regimen and increasing the chance for error. Understanding the different types of inhalers highlights the importance of pharmacist counseling for patients who use inhalers. Below are explanations of the differences between using, cleaning, and storing a metered-dose inhaler (MDI), a dry powder inhaler (DPI), and a nebulizer. Pharmacy technicians can point out that every inhaler has an information sheet where patients can find specific and additional instructions. Technicians should encourage patients to read them.

 

DPI⁵⁸

The DPI contains preset doses of medications in powder form. The medicine is released into the airways with deep, fast breaths. The DPI may be easier than the MDI for patient use.  However, patients with really low lung function or small children may not be able to generate enough inspiratory flow to effectively get the medications. Patients do not need to coordinate breathing and using the inhaler with a DPI .

 

• Instructions for use:
  • Open the cover. Hold the inhaler as shown on instructions.
  • Load a dose of medicine as shown in your instructions. Do not tip or shake the inhaler.
  • Stand or sit up straight.
  • Holding the inhaler away from your mouth, breathe out completely to empty your lungs.
  • Place the mouthpiece of the inhaler in your mouth. Close your lips around it to form a tight seal.
  • Take a fast, deep, forceful breath in through your mouth. Take as big of a breath as possible.
  • Hold your breath and count to 10.
  • Take the inhaler out of your mouth. Breathe out slowly.
  • If you need more than one puff, wait 1 minute between puffs. Repeat steps 2-8 for each puff.
  • When you finish close the cover. Store in a cool, dry place.
  • If the medicine is an inhaled corticosteroid, rinse your mouth with water and spit it out. This helps prevent infection.
  • Some multi-dose DPI have a built-in counter to tell you how many doses are left. When the counter gets to “0,” throw it away. Arrange your refill pick-up before it gets to 0.
• Instructions to clean the DPI
  • Wipe the mouthpiece at least once a week with a dry cloth
  • Do not use water to clean to DPI

 

MDI⁵⁹

The MDI is a canister of medication placed into an actuator inhalation mouthpiece. Every use of the MDI delivers the correct amount of medication.

• Instructions for use:
  • Take off the cap, shake the inhaler. Prime the inhaler (if needed)
  • If a spacer* is used, place the inhaler in the rubber ring on the end of a spacer
  • Stand or sit up straight
  • Breathe out completely to empty your lungs
  • Place the mouthpiece in your mouth and close your lips around it to form a tight seal
  • While breathing in, press down firmly on the top of the canister to release one “puff,” or dose of medication. Take as big of a breath as possible, breathing in slowly for 3-5 seconds.
  • Hold your breath and count to 10.
  • Take the mouthpiece out of your mouth. Release your breath.
  • If you need more than one puff, wait 1 minute between puffs. Repeat steps 3-8 for each puff.
  • Put the cap back on the inhaler.
  • If the medicine is an inhaled corticosteroid, rinse your mouth with water and spit it out.This helps prevent infection.
• Important cleaning instructions:
  • Do not put the medicine canister in water
  • Do not brush or wipe the inside of the inhaler

A “spacer” is a tube or chamber that adds distance between the mouth and the canister of medication. The device increases the ease of administering medication.

 

 

Nebulizers⁶⁰

Nebulizers change liquid medication into an aerosol. Nebulizers come in both home and portable sizes. Nebulizers need a power source. They plug into a wall, have chargers, or need batteries replaced. Nebulizers take longer to use than MDI or DPI. They are also more laborious to use and store.

 

• Instructions for use:
  • Wash hands well.
  • Put together the nebulizer machine, tubing, medicine cup, and mouthpiece or mask as shown in instructions.
  • Put the prescribed amount of medicine into the nebulizer cup.
  • Place the mouthpiece in your mouth and close your lips around it to form a tight seal. If a child wears a mask, make sure it fits in snugly around the child’s face and covers their mouth and nose.
  • Turn on the nebulizer machine. You will be able to see a light mist coming from the back of the tube or from the mask.
  • Take normal breaths through the mouth until the medicine cup is empty or the mist stops. This should take about 10 minutes.
  • Take the mouthpiece out of your mouth (or the child’s mouth) and turn off the machine.
  • If the medicine is an inhaled corticosteroid, rinse your mouth with water and spit it out. This helps prevent infection. If a child uses a mask, wash the face as well.
• How to clean and store:
  • After each treatment
    • Wash hands well.
    • Wash the medicine cup and mouthpiece/ mask with warm water and mild soap.
    • Do not wash tubing.
    • Rinse well and shake off excess water.
    • Air dry parts on a paper towel.
  • Once a week:
    • Disinfect nebulizer parts to help kill any germs. Use the instructions that come with your device.
    • Do not wash or boil the tubing.
    • Air dry parts on a paper towel.
  • Between uses:
    • Store nebulizer parts in a dry, clean plastic storage bag.
    • If the same machine is used by more than one person, keep each person’s medicine cup, mouthpiece or mask, and tubing in a separate, labeled bag to prevent the spread of germs and medication errors.
    • Wipe surface with a clean, damp cloth as needed.
    • Replace parts as stated in the instructions or when they appear damaged.

 

“When you’re riding in a Chevy and you feel something heavy.

When you’re sliding into home and your pants are full of foam.

When you’re sitting in the bath and you feel something splash.”¹

No one likes to talk about it, but everyone knows what it is. Some call it "Montezuma's revenge," "the runs," or worse. Although diarrhea is one of the most commonly managed medical conditions in the outpatient setting, it can also be one of the most serious if treated inappropriately. In addition, concerns with older approaches to acute diarrhea have led to several new practice recommendations. The novel coronavirus disease-2019 (COVID-19) pandemic is also associated with a significant gastrointestinal (GI) component. In one early United States (U.S.) study of patients with COVID-19, one third reported GI symptoms prior to the onset of fever or respiratory symptoms.²

Another challenge is the escalating opioid crisis. Patients addicted to opioids are now abusing over-the-counter (OTC) antidiarrheal medications, such as loperamide, to help manage withdrawal symptoms. The purpose of this activity is to highlight several recent changes in diarrhea management and provide an overview of commonly used OTC antidiarrheal agents and other treatment strategies.

The classic definition of diarrhea is passage of loose or watery stools. Some have defined it as the passage of three or more watery stools per day, but it is difficult to define absolute limits. Acute diarrhea typically lasts one to two days (starting with the first loose stool, not when treatment starts). Patients and caregivers should raise concerns whenever stool patterns deviating from the norm are accompanied by other signs of illness, not just based on the stool frequency or water content. Table 1 summarizes the most common symptoms associated with acute diarrhea.

Table 1. Symptoms Associated with Acute Diarrhea³

• Abdominal pain
• Cramping
• Fecal incontinence
• Fecal urgency
• Nausea
• Three or more loose, watery stools daily

In the U.S., approximately 179 million cases of acute diarrhea occur annually.⁴ The following sections describe its many causes. In immunocompetent individuals, the primary etiology of infectious diarrhea includes foodborne pathogens and norovirus outbreaks.⁵

Numerous factors predispose patients to developing acute diarrhea (see Table 2). Providers should not confuse acute diarrhea with chronic diarrhea (i.e., diarrhea lasting more than two weeks). In many instances, the etiology of acute diarrhea is unknown and it resolves without treatment. Acute diarrhea is most commonly infectious in nature or related to a medication adverse effect.

Table 2. Causes of Acute Diarrhea

Cause	Description
Excessive intake of artificial sweeteners	Mannitol, sorbitol, xylitol (found in sugar-free products)
Food intolerance	Lactose intolerance
Infections	Bacterial (e.g., E. coli, Salmonella)
	Parasitic (e.g., Giardia, Cryptosporidium, E. histolytica)
	Viral (e.g., COVID-19, norovirus, rotavirus)
Medications	See Table 3
Travel (typically to developing countries)	Consuming food or drink contaminated by bacteria or parasites

COVID-19 = coronavirus disease-19

INFECTIOUS CAUSES OF DIARRHEA 

Viral Gastroenteritis

Acute infectious diarrhea is often viral, resulting in more than 1.5 million outpatient visits in the U.S. annually.⁵ Typically, patients with viral diarrhea experience low-grade fevers and watery, non-bloody diarrhea lasting one to two days. Rotavirus used to be the most common cause of diarrhea in the U.S., but as rotavirus vaccination rates have increased, norovirus has taken over this title. Infant rotavirus immunization starts as early as six weeks of age but no later than 15 weeks.⁶ Healthcare providers should administer the final dose in the immunization series by eight months of age. Infants infected with rotavirus prior to receiving the full vaccine course should still initiate or complete the recommended schedule, as initial infection confers only partial immunity.

Norovirus-induced diarrhea is less severe than rotavirus, especially in children. More commonly known as the “cruise ship virus,” norovirus is now one of the leading causes of foodborne disease and a common cause of traveler’s diarrhea.⁷ Vomiting often accompanies diarrhea. In most cases, symptoms appear 12 to 48 hours after exposure and last one to three days, although the virus can continue to be shed in stools up to two weeks after resolution. Interestingly, not everyone is susceptible to norovirus infections. Individuals with type O blood are more prone to norovirus infections, while those with type B blood are least likely to contract them.⁸

Bacterial Gastroenteritis

It is sometimes difficult to distinguish between viral and bacterial gastroenteritis. Unlike viral gastroenteritis, bacterial infections associated with diarrhea have the potential to be more severe and are often associated with high fevers (exceeding 104^oF), abdominal pain, and bloody stools.⁵ Vomiting is less common. The most common causes of bacterial gastroenteritis in the U.S. are non-typhoidal Salmonella and Campylobacter species.⁵ These usually occur after eating raw or undercooked poultry or something that came in contact with it. Reptiles, such as pet turtles, can also carry Salmonella in their stool and easily transmit the bacteria to their shells, tank water, and anywhere else they live and roam.⁹

Bacterial gastroenteritis is usually mild and self-limiting, but infants younger than three months of age may experience severe complications that can result in hospitalization.⁶ In an otherwise healthy individual, bacterial gastroenteritis can resolve without any treatment. Antibiotics are reserved for treating diarrhea in immunocompromised patients, infants younger than three months of age, and patients who appear septic or toxic.^5,6

COVID-19-Related Diarrhea

Since the onset of the COVID-19 pandemic, respiratory symptoms have been the most common presentation of this viral illness. A growing number of patients, however, experience GI symptoms (e.g., anorexia, diarrhea, nausea, vomiting), sometimes without respiratory symptoms. COVID-19-induced diarrhea can last one day to as long as two weeks.² Although the mechanisms involved in the pathogenesis of COVID-19-related diarrhea are still unknown, the virus is likely altering intestinal permeability resulting in enterocyte malabsorption.¹⁰

Foodborne Disease

Produce—especially leafy green vegetables—is the most common source of diarrhea due to foodborne pathogens.¹¹ Spinach and lettuce purchased from grocery stores often come from developing countries where water contamination is common and produce does not undergo agricultural inspection. Diarrhea-producing E. coli or Salmonella are common pathogens. Contaminated poultry is associated with the highest proportion of diarrhea fatalities (19%), mainly due to Salmonella or Listeria infection.¹¹

To reduce this risk, consumers should soak leafy greens in water and rinse them thoroughly before eating. They must also use care when handling raw poultry. To prevent cross-contamination, cooks should prepare raw poultry separately from other foods. They should also clean food preparation surfaces and utensils (e.g., counters, cutting boards, forks, knives) and their hands with hot, soapy water after handling raw poultry. Finally, they must cook all raw poultry thoroughly. Updated weekly, the Centers for Disease Control and Prevention (CDC) provides extensive information on foodborne outbreak investigations on their website: https://www.cdc.gov/foodsafety/outbreaks/index.html.

Traveler’s diarrhea—commonly caused by consuming contaminated food or drinking water in foreign countries—often appears within 10 days of travel to an area with poor public hygiene.¹² In most cases, traveler’s diarrhea is not serious. However, in some instances, this type of diarrhea may last longer than usual due to infections with parasites and requires treatment with an antiprotozoal agent.¹³ Although it can occur anywhere, the areas of greatest risk are in Africa, Asia (except Japan and South Korea), Central and South America, Mexico, and the Middle East.¹⁴ The CDC publishes notices for travelers about potential health implications (e.g., disease outbreaks, gatherings, natural disasters) for destinations around the world, sorted by disease or country.¹⁵

 

NON-INFECTIOUS CAUSES OF DIARRHEA

Medication-Associated Diarrhea

Many medications can cause diarrhea as a side effect, usually because they affect gut motility or microbe balance.

Antibiotic-associated diarrhea

Antibiotic-associated diarrhea (AAD) results from an imbalance of intestinal bacteria where opportunistic bacteria like C. difficile are allowed to thrive.¹⁶ AAD happens during a course of antibiotics or shortly afterward. The most commonly implicated antibiotics include clindamycin, macrolides, and other broad-spectrum antibiotics, but any antibiotic can disrupt the balance of non-pathogenic bacteria flora within the intestines.

Pharmacy staff may field questions about fecal transplants (also known as “poop pills” or “poop with a purpose”). The formal name for this is fecal microbiota transplant (FMT), which entails transferring stool from a healthy individual to a patient infected with C. difficile. The goal is to restore the balance of bacteria in the infected patient’s gut. In patients with recurrent C. difficile infections, FMT may be more effective and significantly less expensive than a course of vancomycin.¹⁷ It is not an approved therapy, but the FDA does allow clinicians to use it investigationally to treat C. diff infections. It is not without risk, and patients have developed life-threatening infections from FMT contaminated with other pathogenic organisms.¹⁸

PAUSE AND PONDER: How can Halloween candy and fruit juices predispose children to diarrhea?

Table 3 lists drugs that can cause acute diarrhea. Pharmacists should refer patients to their prescribers to discuss therapeutic alternatives without diarrheal adverse effects. For example, magnesium-containing OTC antacids may cause diarrhea, but calcium carbonate and aluminum hydroxide do not, making them suitable alternatives. Likewise, herbals, such as St. John’s wort, aloe vera juice, and lobelia, have been linked with diarrhea.

Table 3. Drugs Associated with Acute Diarrhea¹⁹

Medication Class	Examples
Antibiotics	·         Cephalosporins (e.g., cefdinir, cefpodoxime) ·         Clindamycin ·         Macrolides (e.g., erythromycin, clarithromycin, azithromycin, fidaxomicin) ·         Penicillins (e.g., amoxicillin, ampicillin)
Cancer chemotherapeutics	·         Cyclophosphamide ·         Daunorubicin ·         Epirubicin ·         Fluorouracil ·         Gemcitabine ·         Ixabepilone ·         Methotrexate ·         Vincristine
Copper chelators	·         Dimercaprol ·         Penicillamine ·         Trientine
Corticosteroids	·         Dexamethasone ·         Prednisone
Digitalis glycosides	·         Digoxin
Magnesium salts	·         Magnesium hydroxide (Phillips’ Milk of Magnesia, Ducolax Milk of Magnesia, Pedi-lax Chewable Tablets)
Mood stabilizers	·         Lithium
Nonsteroidal anti-inflammatory agents	·         Ibuprofen ·         Meclofenamate sodium
Proton Pump Inhibitors	·         Lansoprazole ·         Omeprazole ·         Pantoprazole

Laxative-Associated Diarrhea

Laxative-associated diarrhea is a specific form of medication-associated diarrhea.²⁰ Excessive intake of laxatives could be accidental (e.g., not understanding the directions) or intentional (e.g., child abuse, bulimia, anorexia nervosa). For example, there are cases reports of parents hiding laxatives in children’s food and/or medication as part of an ill-advised prank or an abusive gesture, resulting in serious harm.^21,22 A person buying multiple types and/or large quantities of laxatives or asking inappropriate questions about their use may be misusing them. Obtaining a thorough history and encouraging patients and caregivers to seek medical care is just as, if not more, important than recommending an antidiarrheal agent. When possible, pharmacy team members may want to discuss their observations regarding unusual laxative use with the patient’s PCP.

 

Toddler Diarrhea

Toddler diarrhea—also known as functional diarrhea or non-specific diarrhea of childhood—often occurs when children drink considerable amounts of hyperosmolar fluids, such as fruit juices. According to the American Academy of Pediatrics, toddlers between one and three years of age should limit their juice intake to no more than four ounces per day.²³ Toddler diarrhea management involves reducing the volume of fruit juices or other osmotically-active carbohydrate beverages that contain sorbitol or fructose. Similarly, children may develop self-limiting “Halloween diarrhea” after ingesting sorbitol- and fructose-rich candies.²⁴

Lactase Deficiency or Food Intolerance

The brush border of the small intestine produces the enzyme lactase. It is necessary for breaking down lactose (“milk sugar”) to digest milk.​ Lactase deficiency can occur when an enteric (intestinal) infection causes mucosal (lining) injury. Approximately 68% of the world's population has some form of lactose malabsorption.²⁵ Lactase deficiency is more prevalent in Asia and Africa, while it occurs less frequently in northern Europe where many people carry the gene that codes for lactase.²⁶ About 36% of Americans have some form of lactose malabsorption.

When lactose malabsorption occurs with a case of acute viral gastroenteritis, it tends to be mild and self-limiting. Regardless of the cause, when patients have inadequate lactase, ingested lactose is malabsorbed and gut bacteria use it as an energy source and to produce gas. Moreover, undigested lactose has an osmotic effect and pulls excessive water into the bowel, resulting in diarrhea.²⁵ Patients experience abdominal pain, flatulence, or diarrhea within several hours of ingesting a significant lactose load, and it resolves after several days of avoiding lactose-containing foods.

Other forms of food intolerance can also cause diarrhea. Drinking overly salted beverages and ingesting excessive fiber (e.g., sunflower seeds) can cause diarrhea.²⁷ Hot peppers (e.g., jalapeño peppers, cayenne peppers, and some chili peppers) contain the chemical irritant capsaicin (responsible for the “burn") which can trigger diarrhea.²⁸ Similarly, onions and large amounts of spices, fruits, and vegetables can also predispose patients to dietary diarrhea.²⁷ Avoiding the causative food is the best approach to managing symptoms.

PAUSE AND PONDER: How does an antidiarrheal alter the symptoms associated with diarrhea?

 

DIARRHEA TREATMENT AND PREVENTION

Some recommendations for diarrhea are the same across the board, while others are on a case-by-case basis. In cases of infectious diarrhea, all pharmacy staff should emphasize the need for good hand hygiene, especially after using the bathroom or performing diaper changes to protect others from becoming infected. People should wash their hands with soap and water for at least 15 to 30 seconds paying special attention to the fingernails, between fingers, and wrists. Alcohol-based hand sanitizers are ineffective at preventing all types of diarrhea (i.e., norovirus, Clostridiodes).²⁹ People must also use soap and water to wash visibly soiled hands. In cases of COVID-19 infection, experts recommend using an alcohol-based rub that contains at least 60% alcohol in addition to soap and water.³⁰ Pharmacy teams should be prepared to help patients and caregivers select appropriate diarrhea treatments.

Oral Rehydration Solutions

Provided they are able to drink, most patients with mild-to-moderate dehydration should use oral rehydration solutions (ORSs) to manage diarrhea symptoms. Although ORSs do not treat diarrhea, they help prevent dehydration and electrolyte losses. ORSs are safer, inexpensive alternatives to intravenous fluids. They contain dextrose and electrolytes to replace fluid and electrolytes. The dextrose in ORSs enables the intestine to absorb fluid and salts more effectively.³¹ Table 4 describes commonly-used ORS products. Breastfed infants should continue to drink breastmilk during the bout of diarrhea.

Table 4. Comparison of Oral Rehydration Solutions^31,32

	WHO Reduced-Osmolarity ORS	Pedialyte	Cerelyte 70	Gatorade	G2 + ½ teaspoon table salt
Glucose	28 g/L	25 g/L	40 g/L*	58 g/L	28 g/L
Sodium	75 mEq/L	45 mEq/L	70 mEq/L	23 mEq/L	63 mEq/L
Potassium	20 mEq/L	20 mEq/L	20 mEq/L	< 1 mEq/L	3 mEq/L
Citrate	10 mEq/L	30 mEq/L	30 mEq/L	None	None
Chloride	65 mEq/L	35 mEq/L	60 mEq/L	17 mEq/L	32 mEq/L
Osmolarity	311 mOsm/L	250 mOsm/L	220 mOsm/L	280-360 mOsm/L	254 mOsm/L

G2 = G2 Gatorade; ORS = oral rehydration solution; WHO = World Health Organization

*as rice base

Pharmacy staff should advise patients to avoid tea, rice water, fruit juice, or gelatin as ORS substitutes, as they contain insufficient electrolytes and may be too hypertonic which could worsen diarrhea. Given the widespread availability of premixed products, people should not try to prepare their own ORS. Pharmacy staff should caution patients to avoid using sports drinks as ORS, as these products contain significant amounts of sugar and can exacerbate diarrhea. Furthermore, if the patient is experiencing significant vomiting or diarrhea, sports drinks contain inadequate amounts of electrolytes, such as sodium, and cannot effectively replace losses.

In the event a commercial ORS product is unavailable, some have recommended adding table salt to G2 Gatorade (not regular Gatorade) to increase its sodium content to match traditional ORSs.³² This option, however, is prone to error and adding too much salt is just as detrimental as not adding enough. Some errors in making homemade ORS have been fatal.³³

 

Dietary Measures

The practice of holding solid foods and dairy products for the first 24 hours after acute diarrhea onset has come under scrutiny.³⁴ In patients who are adequately hydrated, food is allowed. Caregivers can provide bland, easily-digestible foods and beverages for the first 24 hours after diarrhea onset in patients with nausea or vomiting. Pharmacy teams should advise patients and caregivers to withhold food if antiemetics are unable to control vomiting.

Individuals may read they should eliminate specific foods while they have diarrhea. Patients should avoid foods rich in fructose (e.g., fruit juices), as they are often difficult to digest.³⁵ Similarly, sugar-sweetened drinks can worsen diarrhea, cramping, and flatulence. Most juices also contain little fiber and, in comparison to whole fruits, offer no nutritional advantage. Because they may stimulate bowel function, patients should avoid foods containing roughage (e.g., beans, Brussels sprouts, cabbage), as these may exacerbate diarrhea. Instead, during a bout of diarrhea, patients should follow a low-fiber diet limiting dietary fiber intake to 10 grams/day.³⁶ Table 5 describes foods that are appropriate during episodes of diarrhea and foods to avoid.

Table 5. Foods that Should Be Avoided or Allowed During Bouts of Diarrhea^{35, 36}

Foods to Avoid	Foods That Are Permitted
·  Alcohol ·  Dairy products (if lactose intolerant) ·  Foods containing artificial sweeteners (sorbitol, mannitol, and xylitol) ·  Foods high in roughage (e.g., beans, broccoli, Brussels sprouts, cabbage, cauliflower) ·  Fructose-containing products ·  Fruits (e.g., apples, peaches, pears) and fruit juices ·  High-fat, greasy foods ·  Spicy foods	·  Applesauce ·  Baked chicken with skin removed ·  Bananas ·  Boiled or baked potatoes with skin peeled ·  Bread or toast ·  Chicken soup ·  Hot cereals (e.g., cream of wheat, oatmeal) ·  Plain white rice ·  Unseasoned crackers

Some people use astringent herbs and teas rich in tannins (e.g., blackberry, raspberry teas) as a treatment for diarrhea. When treating diarrhea, only dried berries or juice are recommended, as fresh berries may actually exacerbate symptoms.³⁷ Moreover, patients should be aware that in large doses, blackberry tea might cause more GI upset and trigger nausea and vomiting. Pregnant women should use raspberry and raspberry leaf preparations with caution as they may stimulate contraction of uterine tissue.³⁸

BRAT Diet

This diet is intended to manage diarrhea by providing a bland diet that may improve diarrhea symptoms. However, its low nutritional content has resulted in its abandonment.³⁹ Similarly, only providing clear liquids for several days can potentially prolong the duration of diarrhea, a condition often referred to as “starvation stools.”⁴⁰ This form of diarrhea is green and watery. The green bile is excreted into the stool when there is no food to digest. It is not harmful and management simply entails increasing food intake.⁴¹ Pharmacy teams should not recommend the BRAT diet to patients with diarrhea, as it is outdated.

Probiotics and Prebiotics

To prevent or treat antibiotic-associated diarrhea, healthcare providers often recommend probiotics (see Table 6 for examples). Probiotics—microorganisms that replace colonic bacteria—suppress pathogenic microorganisms’ growth thus restoring normal intestinal function. The most commonly used probiotics to decrease the duration and severity of diarrheal episodes include Saccharomyces boulardii, Lactobacillus GG, and Lactobacillus acidophilus. Some foods contain naturally-occurring probiotics, but probiotic supplements are also available.

Table 6. Examples of Probiotics⁴⁴

Type	Examples
Probiotic-containing foods	aged soft cheeses beet kvass cottage cheese dark chocolate green olives kefir kimchi kombucha	miso natto pickles sauerkraut sourdough bread tempeh yogurt
Align Resistance Formula Capsule	10 Billion CFU of Saccharomyces boulardii CNCM1-1079
Culturelle Capsule	Lactobacillus GG 10 billion CFU Inulin (chicory root extract) 200 mg Vitamin C 3 mg
FlorastorPre Capsule	Prebiotic and probiotic blend: Saccharomyces boulardii lyo CNCM I-745 250 mg Prebiotic fiber (chicory root –inulin) 300 mg
Physician’s Choice Probiotics 60 billion CFU (per serving)	10 Probiotic strains (220 mg): Lactobacillus casei Lactobacillus acidophilus Lactobacillus paracasei Lactobacillus salivarius Lactobacillus plantarum Lactobacillus bulgaricus Bifidobacterium lactis Bifidobacterium bifidum Bifidobacterium longum Bifidobacterium breve	Prebiotic fiber blend: Jerusalem artichoke root 50 mg Gum Arabic (Fibergum Bio) 50 mg Chicory Root powder 50 mg

One meta-analysis showed probiotic use may prevent antibiotic-induced diarrhea in adults but was not effective in those older than 65 years of age.⁴² To be most effective, patients should start probiotics early when signs of diarrhea first appear. Patients who are also receiving antibiotics should separate probiotic administration by at least two hours from the antibiotic dose. Evidence supporting probiotic use in managing viral diarrhea is mixed.⁴³

Typically used in combination with probiotics, prebiotics are oligosaccharides that stimulate growth of commensal intestinal bacteria (i.e., naturally-occurring flora that induce protective responses to prevent pathogen invasion and colonization). Data supporting the use of prebiotics to reduce severity or duration of diarrhea is weak, and they are not universally recommended.⁴⁵ Currently, prebiotics are only available in combination products containing a probiotic.

Bismuth Subsalicylate

Patients use bismuth subsalicylate (Pepto-Bismol) to treat mild, nonspecific diarrhea. It has anti-secretory, anti-inflammatory, and antimicrobial properties.⁴⁶ Developed more than 100 years ago by a physician to treat cholera, it was originally called Mixture Cholera Infantum.⁴⁷ Despite its cheery pink color, pharmacy staff should remind patients and caregivers that bismuth subsalicylate can darken the stools and tongue with repeated use. Typical dosing for patients older than 12 years of age for acute diarrhea is 524 mg every 30 to 60 minutes or 1,050 mg every 60 minutes as needed for up to 2 days (maximum: 4,200 mg/24 hours).^46,47  Most patients will experience relief within 30 to 60 minutes of a dose. Children and adolescents who have or are recovering from influenza or chicken pox should not use bismuth subsalicylate due to the association of Reye syndrome.^46,47

Patients with histories of salicylate allergy, coagulopathy, or ulcers should not use bismuth subsalicylate. Patients receiving anticoagulants or medications for gout or arthritis (e.g., allopurinol, colchicine, ibuprofen, indomethacin, naproxen) should also avoid it. It can bind with tetracyclines and may also interfere with GI contrast studies. Use of bismuth subsalicylate during a contrast study can potentially cause misinterpretation of images and decrease the test's sensitivity.⁴⁸ Because it is hyperdense liquid, it can mimic the appearance of an acute GI bleed, which may lead to potential diagnostic errors. Patients taking bismuth subsalicylate must also stop using this product if they develop ringing or buzzing in the ears (i.e., tinnitus) because it indicates salicylate toxicity.

Loperamide

Loperamide (Imodium A-D) is an opioid-receptor agonist that inhibits peristalsis (muscle contractions in the GI tract) by acting directly on the musculature of both the small and large intestine.⁴⁹ It has been available OTC since 1988. Typical OTC dosing is 4 mg, followed by 2 mg after each loose stool.⁴⁹ At the Food and Drug Administration (FDA)-recommended OTC maximum dose of 8 mg per day, it does not predispose patients to the usual side effects associated with opioid use (e.g., euphoria, lethargy, nausea, vomiting). Patients should limit use to fewer than two days unless they are receiving medical supervision. Most patients will see improvement in symptoms within one hour after a dose.⁴⁹ Caregivers should not give loperamide to children younger than three years old, as there are case reports associating it with toxic megacolon (severe swelling of the colon) and ileus (intestinal obstruction).⁴⁹

When taken at recommended doses, loperamide does not cross the blood-brain barrier or yield the “high” seen with other opioids. However, at extremely excessive doses (i.e., more than 100 to 200 mg/day), loperamide enters the central nervous system and produces effects similar to those associated with centrally-acting opioids like heroin, hydrocodone, or morphine.⁴⁹ Some individuals withdrawing from opioids use loperamide to ameliorate their symptoms, or simply to induce euphoria.

Loperamide overdoses have been associated with serious cardiac complications, including arrhythmias, loss of consciousness or fainting, and myocardial infarction. Moreover, even standard doses of loperamide may interact with medications that can cause QT prolongation such as azole antifungal drugs and macrolide antibiotics. In response to these concerns, in September 2019, the FDA approved changes to OTC loperamide products. These changes limit each container to no more than 48 mg of loperamide and require the tablets and capsules to be individually packaged (i.e., unit-dosed).⁵⁰

Supplements

Many patients prefer to use OTC supplements to prevent or treat diarrhea. For this indication, a variety of natural products and enzyme supplements are used.

Lactase Enzymes

For individuals prone to diarrhea due to lactose intolerance, lactase enzymes are beneficial for prevention.⁵¹ Most lactose intolerant individuals do not have to give up all dairy products, as they can manage their symptoms by using lactase supplements or lactase-fortified products. There are several ways to provide lactase, and Table 7 lists commonly available products. The typical dose of lactase supplementation to prevent diarrhea in intolerant individuals is 6000 to 9000 international units at the start of a lactose-containing meal.⁵¹ Some patients prefer to add lactase supplementation to milk. In this case, patients mix 2000 international units of a lactase solution into 500 mL of milk immediately before drinking.

Table 7. Common Lactase Supplements

Tablet, Oral	Tablet Chewable, Oral	Drops (added to liquid dairy products)	Powder
Lactaid: 3000 units Lactaid Fast Act: 9000 units Lactase Enzyme: 3000 units Lactase Fast Acting: 9000 units Surelac: 3000 units	Lactaid Fast Act: 9000 units Milkaid: 3000 units	Elepure lactase drops: 750 units per 5 drops Seeking Health Lactase Drops: 750 units per 7 drops	Nutricost Lactase Powder: 10,000 units per 10 grams

Zinc

Zinc supplements reduce the duration of a diarrhea episode by 25% and are associated with a 30% reduction in stool volume.⁵² Zinc is available in a variety of salt forms, including zinc-gluconate, -acetate, -ascorbate, -chloride, and -sulfate. Providers may use zinc to manage acute diarrhea in children older than six months of age, but evidence supporting its efficacy is mixed. According to the World Health Organization, patients should start zinc supplementation in conjunction with ORS at the first sign of diarrhea, as it may shorten the duration and severity of episodes and prevent subsequent episodes.⁵³ In infants younger than six months of age and children, providers sometimes use doses of 20 mg elemental zinc once daily for 10 to 14 days. The most common adverse reactions associated with oral zinc include dysgeusia (altered taste), mouth irritation, nausea, and vomiting.

Goldenseal/Berberine

Capsules of dried goldenseal appear to kill many bacteria that cause diarrhea, including E. coli. The key component in the herb is berberine. In addition to its antimicrobial effects, berberine may reduce diarrhea by enhancing sodium and water absorption by the intestinal lumen.⁵⁴ In animal models, berberine appears to slow GI motility by activating opioid pathways.⁵⁵

Doses of goldenseal used in studies vary considerably, from 250 mg to 1 g administered three times daily.⁵⁶ Studies of berberine taken alone used doses of 300 to 500 mg three times daily.⁵⁷ Typically, patients take goldenseal capsules daily until diarrhea improves. Patients should be aware that, although rare, very high doses of goldenseal may cause anxiety, depression, nausea, paralysis, or seizures.⁵⁸ Goldenseal may also affect the cytochrome P450 system and may alter patient response to medications metabolized by those enzymes.

Psyllium

Ground psyllium seeds are found in the flowering plant of the plantago genus absorb excess fluid in the intestines. Patients often use psyllium to treat constipation, so patients may be unaware that it can help with diarrhea too. Typical doses are one to three tablespoons mixed in water each day, but the product is also available as capsules and wafers.⁵⁹ When taken concurrently, psyllium may bind with some medications (e.g., carbamazepine, lithium) and may decrease blood glucose levels, so caution is advised in patients taking antidiabetic agents. Adverse effects associated with psyllium use include bloating, flatulence, indigestion, nausea, and vomiting.

PAUSE AND PONDER:  Why are sports drinks not used for fluid and electrolyte replacement in patients experiencing diarrhea?

UNSAFE OR INEFFECTIVE TREATMENTS

Complementary and alternative medicine refer to those medical products that are not standard of care. Many patients will use “home remedies” to manage their symptoms, employing special diets or supplements to manage bouts of diarrhea. In many instances, insufficient evidence exists to support their safety or efficacy. Pharmacy teams should be aware of the more commonly used remedies in their geographic locations (as they vary by population) and understand their limitations.⁶⁰

Wood-Tar Creosote

Some alternative medicine circles use wood-tar creosote (found in a product called Seirogan) as an antidiarrheal treatment. Wood creosotes come from the resin of the leaves of the creosote bush and beechwood.⁶¹ In its classic form, it is a dark brown round pill, but a sugar-coated tablet is also available that masks its bitter taste and distinct medicinal odor. It is not a benign therapy, as ingesting high levels of creosote may cause burning in the mouth and throat or gastritis. Moreover, creosote may be carcinogenic with long-term use. Pharmacy teams should communicate these risks to patients seeking to use wood-tar creosote and encourage them to use a safer alternative.

Attapulgite

Attapulgite is a naturally-occurring, orally-administered clay named for the U.S. town of Attapulgus, Georgia, where it is abundant.⁶² It is a non-absorbable medication that adsorbs large numbers of bacteria and toxins and thereby reduces fluid loss.⁶³ Its binding action reduces the frequency of bowel movements and improves the consistency of stools. Attapulgite can absorb eight times its weight in water. It used to be present in Kaopectate, but in 2003, the manufacturer reformulated the product and replaced attapulgite with bismuth subsalicylate as the active ingredient. The FDA did not include attapulgite as a monograph ingredient, citing that efficacy data was inadequate.⁶⁴ Attapulgite is still used as a veterinary drug in the U.S. and is available in many countries as an OTC antidiarrheal.

“RED FLAGS” TO REFER PATIENTS FOR MEDICAL ATTENTION

Fluids and OTC antidiarrheal products cannot manage all cases of acute diarrhea. Cases accompanied by fever or excessive mucus in the stool suggest evaluation by a primary care provider (PCP) is necessary. Dehydration is another concern, especially in cases where patients report weight loss or decreased urine output (i.e., more than six hours since last urination, decreased number of wet diapers). If patients fail to improve despite oral rehydration, they should seek medical attention.

Patients with a history of recent travel to an undeveloped country, backcountry camping, or consumption of processed meat may develop infectious or parasitic diarrhea. Children in daycare or using community swimming pools may also be at risk for contracting bacterial diarrhea, such as giardiasis. These patients should see their PCPs for further evaluation, as antimicrobial therapy might be necessary.

Toxic exposures to contaminated food, plants, and other substances can cause diarrhea. Obtaining a good history and knowing when to refer patients to their PCPs or hospital is an important step in managing care. For example, profuse diarrhea that occurs with excessive salivation or tearing may be suggestive of organophosphate ingestion.⁶⁵

Although most acute diarrhea cases are self-limiting, children younger than three years of age and adults older than 60 with multiple co-morbidities should seek immediate medical care.⁶⁶ Table 8 highlights other “Red Flags” that warrant immediate medical attention.

Table 8. “Red Flag” Symptoms Indicating Patients Experiencing Diarrhea Should Seek Immediate Medical Attention³

People of All Ages	Infants/Young Children
6 or more loose stools per day Bloody, black, tarry, or pus-containing stools Dizziness or lightheadedness Fever > 102°F and chills Severe pain in abdomen or rectum Vomiting Severe dehydration, evidenced by: Dark urine Decreased skin turgor Fainting/lightheadedness Oliguria (decreased urination) Thirst/dry mouth Severe fatigue Sunken eyes/cheeks	Diarrhea persists > 24 hours < 3 months old: seek medical attention at first signs of diarrhea < 3 months old: any fever Severe dehydration, evidenced by signs in left column, plus: No tears when crying No wet diapers for more than 3 hours Sunken soft spot in an infant’s skull

CONCLUSION

There is no “one size fits all” approach to diarrhea treatment, and pharmacy teams should be prepared to assist patients in selecting the most appropriate approach to manage symptoms. Acute cases of diarrhea usually resolve on their own without treatment, but preventing dehydration is crucial. Before recommending an antidiarrheal agent, pharmacists should obtain a good medication history to avoid potential drug interactions and identify red flags. It is important to remind patients that anti-diarrheal treatments do not necessarily cure the diarrhea, but they help to lessen its severity and duration. Just as important as assisting patients in selecting the best therapy, pharmacy staff can identify when prompt medical attention is necessary. Abuse of antidiarrheal agents is possible, and pharmacists and technicians should be vigilant if they encounter unusual purchasing patterns involving these products.

Download CE Activity