1168 Unit 9 Pharmacology of the Gastrointestinal System
CONNECTIONS: Complementary and Alternative Therapies
Green Tea and Weight Loss
Description antioxidant properties as well as antihypertensive, anti-
inflammatory, antiproliferative, antithrombogenic, and lipid-
Green tea is a natural substance made from the leaves of the lowering effects. Green tea itself contains caffeine, although this
plant Camellia sinensis, which is native to mainland China but is is sometimes removed during processing. Extracts are some-
cultivated worldwide. There are many varieties and types of times standardized to percent polyphenols, which varies widely
green tea. from 14% to 98%, depending on the product. Some products
report the amount of epigallocatechin gallate (EGCG), which is
History and Claims the most abundant catechin in green tea extracts.
In China, green tea has been used for thousands of years for Evidence
ceremonial functions as well as to treat a diverse variety of ail-
ments. In modern times, the health effects of green teas have The administration of green tea extract has been shown to
focused on improving cardiovascular function, weight loss, and decrease body weight. Epidemiologic studies suggest that those
preventing cancer. Some research has examined the role of who consume green tea have a lower percentage of body fat
green tea for improving symptoms or treatment of neurodegen- and lower BMIs than non–tea drinkers. In a randomized, double-
erative diseases such as multiple sclerosis, Parkinson’s disease, blind trial of 115 women with central (abdominal) obesity, weight
and Alzheimer’s disease. loss and decreases in BMI and waist circumference were
observed after 12 weeks of high-dose green tree extract treat-
Standardization ment. This study also demonstrated a consistent trend of
decreased total cholesterol and decreased LDL plasma levels
Green tea extracts contain large amounts of catechins (also (Chen, Liu, Chiu, & Hsu, 2016).
called polyphenols), a group of chemicals that have strong
in adipocytes. Attempts to produce antiobesity drugs that absorption. The decreased lipid absorption lowers calories
block lipid absorption have resulted in one approved drug: and promotes weight loss. Orlistat inhibits fat absorption
orlistat (Alli, Xenical). by approximately 30%.
PROTOTYPE DRUG Orlistat (Alli, Xenical) Pharmacokinetics: PO
Route(s)
Classification Therapeutic: Antiobesity drug Absorption Minimal absorption
Pharmacologic: Lipase inhibitor Distribution
Not distributed; remains in
Therapeutic Effects and Uses: Approved in 1999, Primary metabolism the GI tract; does not cross
orlistat is indicated for the treatment of obesity in combi- Primary excretion the placenta; is not secreted in
nation with a reduced-calorie diet and exercise. Orlistat Onset of action breast milk
is indicated for patients with a BMI of 30 or greater, or Duration of action
a BMI of 27 or greater if the patient has other risk fac- Wall of the GI tract
tors such as HTN, hyperlipidemia, or diabetes. This drug
produces only a modest weight reduction compared to Feces
placebos.
24–48 h
The prescription form of orlistat (Xenical) is available
at 120 mg and is given three times daily, during or up to Half-life: 1–2 h
1 hour after a meal containing fat. An OTC dosage form
(Alli) is approved at 60 mg taken a maximum of 3 times Adverse Effects: Some of the adverse effects of orli-
daily. Orlistat is effective only if taken with meals contain- stat are directly related to its inhibition of lipid absorp-
ing lipids; the dose may be omitted if the meal contains no tion. As more lipids reach the large intestine, flatus with
fat. Orlistat is not approved for individuals under age 12 discharge, oily stool, and fecal urgency are common,
(Xenical) or age 18 (Alli). especially during the first 4 weeks of therapy. To avoid
serious adverse GI effects, patients should restrict their
Mechanism of Action: Orlistat inhibits pancreatic fat intake. Rare cases of liver toxicity have been reported
lipase and acts by blocking lipid absorption in the gas- with this drug.
trointestinal (GI) tract. It primarily lowers the absorp-
tion of free fatty acids but also has an effect on cholesterol Contraindications/Precautions: Orlistat should
be used with caution in patients with cholestasis because
the drug inhibits gallbladder contractions. Orlistat is con-
traindicated for patients who have a known cause of obe-
sity, such as hypothyroidism, and in patients with severe
Chapter 63 Weight Reduction Strategies and the Pharmacotherapy of Obesity 1169
malabsorption disorders. The drug is contraindicated in • Perform a physical assessment including vital signs and
patients with anorexia nervosa or bulimia because it may apometric measurements such as BMI and body weight.
worsen these disorders. Orlistat is contraindicated during
pregnancy because the benefits of weight loss do not out- • Assess laboratory values as indicated to determine
weigh the potential risks to the fetus. hepatic and renal function.
Drug Interactions: Because orlistat inhibits the • Consult a dietitian to prepare and educate the patient
absorption of the lipid-soluble vitamins A, D, and E, a sup- on the recommended nutritional intake.
plement containing these vitamins should be taken at least
2 hours before or after a dose of orlistat. Vitamin K levels • Administer the drug during or up to 1 hour after a
may decrease in patients taking orlistat, which can affect meal containing fat. Omit the dose if eating a meal that
anticoagulation produced by warfarin. Orlistat decreases does not contain fat or if a meal is skipped.
the absorption of cyclosporine and the two drugs should
not be used concurrently. Orlistat may also decrease the • Monitor weight and BMI; closely monitor people with
absorption of warfarin (Coumadin); therefore, coagula- diabetes for hypoglycemia.
tion values in these patients should be monitored closely.
Herbal/Food: Unknown. • Monitor prothrombin time (PT) and international nor-
malized ratio (INR) if the patient is taking warfarin.
Pregnancy: Category X. Assess for signs of vitamin K deficiency such as bruis-
ing or prolonged oozing from minor cuts.
Treatment of Overdose: Overdose with orlistat is
not a clinical problem because the effects of the drug are • Monitor blood pressure frequently, especially in
rapidly reversible. patients with preexisting HTN.
Nursing Responsibilities: • Assess for medications that can interact with orlistat
such as warfarin, cyclosporine, pravastatin, diabetes
• Obtain a complete health history including allergies, drugs, and fat-soluble vitamin supplements such as A,
drug history, and possible drug interactions. D, E, and K. Vitamin deficiencies can occur, causing
changes in eyesight, hair, and skin.
Lifespan and Diversity Considerations:
• Assess the older adult’s diet, medication history, and
alcohol intake. Vitamin deficiency may occur as a
CONNECTIONS: Preparing for Advanced Practice
Obesity in Primary Care
Case changes, she was started on phentermine/topiramate (Qsymia)
for appetite suppression, and canagliflozin (Invokana) was
Sydney is a 42-year-old woman with obesity who has a 9-year added to her medication regimen to help with glucose control.
history of type 2 diabetes. She comes to the clinic with her hus- Sydney returned 6 weeks later with increased energy and was
band, Frank, with complaints of fatigue, difficulty losing weight, ecstatic with her 12-pound weight loss. Her blood pressure
and lack of motivation. Her depression screening is negative. and blood sugar were also well controlled and she let us know
On physical exam, her height is 1.5 m (5 ft 2.5 in.) and her that she has reduced her snacking. Is this treatment plan
weight is 124 kg (275 lb) with a BMI of 50.3 kg/m2. Her blood appropriate for Sydney?
pressure is 160/88 mmHg. The remaining physical findings are
normal. During her first visit, she was counseled on a low- Discussion
calorie, high protein, low-fat, and low-carbohydrate diet, and
was asked to exercise at least 5 times a week. She was also The U.S. Preventive Services Task Force (USPSTF) recommends
instructed on behavioral triggers and coping mechanisms. At that clinicians screen all adults for obesity. Lifestyle and behav-
her 4-week follow-up appointment, she had lost 2.7 kg (6 lb) ioral changes are considered first-line therapies and it is impor-
and her blood pressure was down to 126/85 mmHg. She did tant for patients to maintain them for sustained weight
not seem happy with that and insisted that she be prescribed management. Diet and exercise should remain the gold stan-
the diet pill that her sister was given. Her diet and exercise plan dard of care; however, recent studies suggest that the addition
was reviewed and it was recommended that she continue with of pharmacotherapy may increase the likelihood that patients
the diet and exercise plan for another 6 weeks. Although she will achieve weight loss (more than or equal to 5% of initial
seemed frustrated and asked why her sister did not have to do weight), as compared with brief counseling alone (Carvajal,
all of this, she agreed to the plan. At her 6-week follow-up Wadden, Tsai, Peck, & Moran, 2013). Healthcare providers
appointment she was down an additional 4 pounds! The diet should consider adding pharmacologic management to weight
and exercise plan was continued, and because the lifestyle plan loss treatment plans and, with the new evidence, should feel
had been followed and Sydney had shown positive lifestyle safe in prescribing these medications.
1170 Unit 9 Pharmacology of the Gastrointestinal System
result of normal physiologic changes related to aging warning that it may cause suicidal behavior. It is preg-
and nutrient absorption, alcohol use, or medication. nancy category X.
Medication interactions may be impaired further
with the use of orlistat. Supplementation may be Liraglutide (Saxenda): Liraglutide was initially approved
required. in 2010 for type 2 diabetes. Subsequently, it was approved
in 2014 for weight management in patients with obesity
Patient and Family Education: who have a comorbid condition such as HTN or diabetes.
Like other anorexiants it should be used with a reduced-
• Take a daily multivitamin containing fat-soluble vita- calorie diet and increased physical activity. Liraglutide is a
mins at least 2 hours before or after orlistat. glucagon-like peptide-1 (GLP-1) receptor agonist. GLP-1
helps to regulate appetite by increasing feelings of satiety.
• Adverse GI effects are common but typically resolve Liraglutide has the potential to produce serious adverse
after 4 weeks of therapy. effects such as pancreatitis, hypoglycemia, and gallbladder
disease. The drug is pregnancy category X and carries a
• Avoid high-fat meals to minimize adverse GI effects. black box warning that it may cause thyroid tumors.
Distribute fat calories over three main meals daily. Do
not skip meals. Lorcaserin (Belviq): In 2012, Lorcaserin was approved
for weight loss when combined with a reduced-calorie
• Monitor weight several times weekly. If diabetic, mon- diet and increased exercise. It is believed to act by acti-
itor blood glucose carefully following any weight loss. vating serotonin receptors in the hypothalamus, causing
increased satiety. If a 5% weight loss has not occurred
• Expect that certain adverse effects can occur such as after 12 weeks of therapy, it is recommended that the
stomach discomfort, an increased number of stools, drug be discontinued. Safety and effectiveness in
loss of control of defecation, gas released with bowel patients younger than age 18 has not been established.
movements, oily stools, or the urgent desire to Lorcaserin does produce euphoria in some patients;
defecate. thus it has some potential for abuse (Schedule IV). This
drug is contraindicated during pregnancy because the
• Increase physical activity as tolerated and approved benefits of weight loss do not outweigh the potential
by the healthcare provider. risks to the fetus.
• Provide the healthcare provider with a list of all drugs Sympathomimetic amines (SAs): The SAs are the old-
and supplements currently taken because orlistat can est drugs for treating obesity. The prototype for this group
interact with other drugs and vitamins. is amphetamine. Adderall, commonly used to treat
attention-deficit/hyperactivity disorder (ADHD), is a
• Immediately notify the healthcare provider of any 75:25 mixture of dextroamphetamine and levoamphet-
known or suspected pregnancy. amine. Evekeo, indicated for weight loss and ADHD, is a
50:50 mixture of the two amphetamines. Other SAs
Drugs Similar to Orlistat (Alli, Xenical) approved for weight management include phentermine,
phendimetrazine, methamphetamine, benzphetamine,
Orlistat is the only lipase inhibitor indicated for obesity. and diethylpropion. For effective weight loss, the SAs
should be combined with a calorie-restriction plan and a
63.7 Anorexiants are drugs used to induce physical exercise regimen.
weight loss by suppressing appetite and hunger.
All of the SAs are CNS stimulants with the ability to
A second strategy to reduce weight is to block parts of suppress appetite. All are controlled substances that can
the nervous system responsible for recognizing and cause physiologic and psychologic dependence. Meth-
reacting to hunger. All the anorexiants have the potential amphetamine is a Schedule II drug that carries a black
to produce serious adverse effects; thus their use is lim- box warning regarding its high potential for abuse. Typi-
ited to short-term therapy. Like the lipase inhibitors, cal weight loss is less than 0.5 kilogram (1 pound) per
anorexiants are prescribed for patients with a BMI of at week and the effects tend to diminish over time due to
least 30 or greater, or a BMI of 27 or greater if the patient tolerance. The SAs have limited clinical usefulness
has other risk factors such as HTN, hyperlipidemia, or because they are only for short-term therapy (several
diabetes. weeks), whereas successful treatment of obesity may
require years. Long-term therapy, or abuse, may cause
Bupropion and naltrexone (Contrave): In 2014, the HTN, cardiac abnormalities, bipolar illness, and other
FDA approved Contrave for the short-term pharmacother- psychoses.
apy of obesity. Bupropion is also approved as an atypical
antidepressant and naltrexone as an opioid agonist. Con-
trave reduces appetite by increasing dopamine activity
and blocking opioid receptors in the brain. Contrave
should be discontinued after 4 months if a weight loss of
less than 5% is observed. The drug carries a black box
Chapter 63 Weight Reduction Strategies and the Pharmacotherapy of Obesity 1171
CONNECTION Checkpoint 63.3 has gained wide acceptance as an artificial sweetener in the
United States. Stevia has a bitter taste when used in large
Orlistat may decrease the absorption of fat-soluble vitamins. From amounts. Safety concerns have caused it to be banned in
what you learned in Chapter 61, describe the types of effects several countries.
that could result from deficiencies in the fat-soluble vitamins A
and D. Answers to Connection Checkpoint questions are available on Fats give food a smooth texture as well as calories. It is
the faculty resources site. Please consult with your instructor. easy to identify fat-free or low-fat foods because they gen-
erally lack the taste and texture of normal fat. Fat substi-
Adjuncts to Obesity Therapy tutes attempt to simulate the texture of normal fat without
the calories or effects of raising lipid levels in the blood.
63.8 Artificial sweeteners and fat substitutes Olestra is a popular fat substitute that consists of a sucrose
are sometimes used as adjuncts to weight molecule surrounded by fatty acids. It has the appeal of fat
management programs. but passes through the digestive tract undigested. It offers
zero calories and zero fat but has the unpleasant adverse
A primary component of any weight management pro- effects of loose stools and anal leakage. It is primarily
gram is reduction of caloric intake. In an attempt to reduce restricted to use in snack foods. Simplesse® is a second fat
total calories, many people have turned to artificial sweet- substitute. It is derived from natural whey protein and is
eners and fat substitutes. used in baked goods and dairy products. Many other prod-
ucts are under development.
Artificial sweeteners include saccharin (Sweet’N
Low®, Sugar-Twin®), aspartame (NutraSweet®, Equal®), Do artificial sweeteners and fat substitutes actually
acesulfame (ACK, Sweet One®, Sunett®), and sucralose help patients lose weight? The answer depends on the
(Splenda®). These agents are 200 to 600 times sweeter dietary habits of the consumer. Certainly, drinking a liter
than table sugar, or sucrose, and thus less quantity is of a regular soft drink gives one many more calories than
needed for sweetening food and beverages. Artificial drinking the same amount of a diet soft drink. Likewise,
sweeteners are regulated by the FDA because they are eating 8 ounces of potato chips using olestra gives fewer
classified as food additives. Safety studies suggest that calories and fat than eating 8 ounces of regular chips.
these substances are safe when used in usual amounts. However, patients with serious weight problems should
Consumers should be aware that “sugar-free” foods that probably make better food choices than soft drinks and
contain artificial sweeteners may have just as many calo- chips. A few studies have suggested that the body com-
ries and have a higher fat content than regular foods. pensates by craving sucrose and high-fat meals. Note that
Patients who have diabetes or are pregnant should con- the FDA has evaluated these food additives only for safety,
sult with their healthcare providers before consuming not for their effectiveness in maintaining or losing body
artificial sweeteners. weight. Just as there are no miracle pills for weight loss,
there are no miracle foods that will promote weight loss.
Stevia (Truvia) is a genus of a plant in the sunflower The answer lies in the simple rules of limiting calorie
family from which natural sweeteners are extracted. More intake, proper nutrition, and exercise.
than 30 times sweeter than sucrose, stevia is recognized by
the FDA as a dietary supplement, not as a food additive. It
Understanding Chapter 63
Key Concepts Summary 63.5 Drugs used for weight management affect appetite
or the absorption of fats.
63.1 Genetic and lifestyle factors contribute to the
etiology of obesity. 63.6 Lipase inhibitors cause weight loss by interfering
with the absorption of fats.
63.2 Appetite is regulated by the satiety center in
the hypothalamus and is influenced by various 63.7 Anorexiants are drugs used to induce weight loss
hormones. by suppressing appetite and hunger.
63.3 Obesity is measured by using the body mass index 63.8 Artificial sweeteners and fat substitutes are
and waist circumference. sometimes used as adjuncts to weight management
programs.
63.4 Nonpharmacologic treatment of obesity should be
attempted prior to initiating pharmacotherapy.
1172 Unit 9 Pharmacology of the Gastrointestinal System
CASE STUDY: Making the Patient Connection
Remember the patient breakfast of “something from the local fast-food place” on the
“Rosemary Goodman” at drive to work, a sandwich at her desk or “whatever the rest of
the beginning of this chap- the office is ordering from take-out” for lunch, and a “regular
ter? Now read the remain- dinner” at home with her husband. On the evenings when her
der of the case study. Based husband is not home for dinner, Rosemary picks up some-
on the information pre- thing at the local supermarket from the prepared food aisle.
sented within this chapter, She also enjoys a glass of wine with dinner. When the nurse
respond to the critical thinking questions that follow. and Rosemary add up the approximate number of calories she
consumes, the average total is over 2000 per day. Rosemary is
Rosemary, a 58-year-old woman, has just had her annual phys- upset and asks the nurse about weight loss strategies.
ical examination with the nurse practitioner. She was shocked
to learn that she has gained just under 13.6 kg (30 lb) since her Critical Thinking Questions
office visit 2 years ago, 7.7 kg (17 lb) in the last year alone. She
went through menopause 2 years ago and thought that some 1. Rosemary asks about diet pills because her mother
of the mild edema and resulting weight gain she experienced used to take them on occasion. What would you tell
around the time of her menses was over. Rosemary has always her about the availability of these drugs today?
been under or at normal weight except for the last office visit.
At the time she was going through a personally stressful time 2. Rosemary would like to try orlistat (Alli), which she has
and was not concerned about the weight gain. She works in an noticed on the shelf in the supermarket. What does Rose-
office as a financial manager, spending most of her day at her mary need to know about orlistat before deciding to take
desk. Although she tries to take lunchtime walks, on most it? What teaching does she need about taking orlistat?
days there is just too much to do in the office.
3. What factors have contributed to Rosemary’s weight
The rest of her physical examination was unremarkable gain during the past 2 years? What general health
except for a borderline hypertensive blood pressure reading of teaching would be appropriate for Rosemary to aid
138/82 mmHg. Her height is 1.6 m (5 ft 6 in.), and she now her in her weight reduction?
weighs 79.5 kg (175 lb). She states that she “watches what she
eats” and normally eats three meals per day: a hurried Answers to Critical Thinking Questions are available on the
faculty resources site. Please consult with your instructor.
Additional Case Study
Kathryn is a 52-year-old woman who has been grossly 1. How would you address Kathryn’s fears about diet
overweight for more than 15 years. In that time she has drugs and the use of orlistat (Xenical)?
tried many diets, exercise regimens, diet clubs, and drug
therapies but all to no avail. She weighs 143 kg (315 lb) 2. How is prescription strength orlistat different from the
and has a BMI of 48. Her healthcare provider has pre- OTC dosage? What adverse effects may occur at the
scribed orlistat (Xenical). She informs you that she has higher dosage?
tried diet pills in the past. She has heard that amphet-
amines cause people terrible problems and is fearful that 3. What effect does orlistat have on vitamin absorp-
she will become dependent on orlistat or experience seri- tion? If Kathryn’s provider prescribes a multivitamin,
ous complications. what should Kathryn know about taking it?
Answers to Additional Case Study questions are available on
the faculty resources site. Please consult with your instructor.
Chapter Review
1. A patient is prescribed lorcaserin (Belviq) for the treat- 2. There is no need to worry about any long-term
ment of obesity and is concerned about the risks effects if they do not occur when the drug is
involved with the drug. Which of the following taken.
should the nurse include when teaching this patient?
3. Begin to see a cardiologist monthly until any
1. If less than a 5% weight loss has been achieved cardiovascular risk has been ruled out.
after 3 months, a different weight loss regimen may
be needed. 4. Contact the drug company about follow-up
programs.
Chapter 63 Weight Reduction Strategies and the Pharmacotherapy of Obesity 1173
2. A patient asks the provider about a prescription for 3. Rise slowly from a sitting or supine position.
phentermine (Adipex-P) for obesity. Which of the 4. Take a daily vitamin supplement containing fat-
following would be considered a contraindication for
the use of this drug? soluble vitamins.
1. Extreme obesity 5. A nurse is instructing a patient taking orlistat (Xeni-
2. A history of type 2 diabetes managed with oral cal) about adverse effects of the medication. Which
symptoms indicate the presence of an expected
antidiabetic drugs adverse effect?
3. A history of hypertension managed with beta
1. Flatus with discharge and oily stool
blockers 2. Heartburn and dyspepsia
4. Pregnancy 3. Constipation with fecal impaction
4. Nausea with projectile vomiting
3. The patient has been started on orlistat (Xenical). The
nurse would teach this patient to take this medication: 6. Which of the following measures is used to assess the
presence of obesity? (Select all that apply.)
1. Once in the morning.
2. When a feeling of hunger is noticed. 1. Body weight
3. Before daily exercise. 2. Body mass index
4. Just prior to each meal containing fats. 3. Waist circumference
4. Treadmill test
4. While taking orlistat (Alli), the nurse would instruct 5. Buoyancy analysis
the patient to do which of the following?
See Answers to Chapter Review in Appendix A.
1. Drink at least 2 to 3 liters of diet soda per day.
2. Always wear sunscreen when outdoors or when
exposed to direct sunlight.
References National Center for Health Statistics. (2016). Prevalence of
overweight, obesity, and extreme obesity among adults:
Carvajal, R., Wadden, T. A., Tsai, A. G., Peck, K., & Moran, United States, 1960–1962 through 2013–2014. Retrieved
C. H. (2013). Managing obesity in primary care practice: from https://www.cdc.gov/nchs/data/hestat/
A narrative review. Annals of the New York Academy of obesity_adult_13_14/obesity_adult_13_14.htm
Sciences, 1281, 191–206. doi:10.1111/nyas.12004
Thompson, J. J., & Manore, M. (2015). Nutrition: An applied
Centers for Disease Control and Prevention. (2016). Adult approach (4th ed.). Upper Saddle River, NJ: Pearson
obesity prevalence maps. Retrieved https://www.cdc. Education, Inc.
gov/obesity/data/prevalence-maps.html
U.S. Food & Drug Administration. (2017). Tainted weight
Chen, I. J., Liu, C. Y., Chiu, J. P., & Hsu, C. H.. (2016). loss products. Retrieved from http://www.fda.gov/
Therapeutic effect of high-dose green tea extract on Drugs/ResourcesForYou/Consumers/
weight reduction: A randomized, double-blind, BuyingUsingMedicineSafely/MedicationHealthFraud/
placebo-controlled clinical trial. Clinical Nutrition, 35, ucm234592.htm
592–599. doi:10.1016/j.clnu.2015.05.003
Selected Bibliography syndrome: An overview. Obesity Reviews, 16(Suppl.1),
1–6. doi:10.1111/obr.12250
Apovian, C. M., Aronne, L. J., Bessesen, D. H., McDonnell, Hopkins, M., & Blundell, J. E. (2016). Energy balance,
M. E., Murad, M. H., Pagotto, U., . . . Still, C. D. (2015). body composition, sedentariness and appetite
Pharmacological management of obesity: An endocrine regulation: Pathways to obesity. Clinical Science, 130,
society clinical practice guideline. The Journal of Clinical 1615–1628. doi:10.1042/CS20160006
Endocrinology & Metabolism, 100(2), 342–362. Kakkar, A. K., & Dahiya, N. (2015). Drug treatment of
doi:10.1210/jc.2014-3415 obesity: Current status and future prospects. European
Dulloo, A. G., & Montani, J. P. (2015). Pathways from
dieting to weight regain, to obesity and to the metabolic
1174 Unit 9 Pharmacology of the Gastrointestinal System
Journal of Internal Medicine, 26(2), 89–94. doi:10.1016/j. biological adaptations. The Lancet: Diabetes &
ejim.2015.01.005 Endocrinology, 3, 232–234. doi:10.1016/
MacLean, P. S., Higgins, J. A., Giles, E. D., Sherk, V. D., & S2213-8587(15)00009-1
Jackman, M. R. (2015). The role for adipose tissue in Polyzos, S. A., & Mantzoros, C. S. (2015). Leptin in health
weight regain after weight loss. Obesity Reviews, 16, and disease: Facts and expectations at its twentieth
45–54. doi:10.1111/obr.12255 anniversary. Metabolism: Clinical and Experimental, 64,
National Institute of Diabetes and Digestive and Kidney 5–12. doi:10.1016/j.metabol.2014.10.017
Diseases. (2016). Types of bariatric surgery. Retrieved Rankin, W., & Wittert, G. (2015). Anti-obesity drugs.
from https://www.niddk.nih.gov/health-information/ Current Opinion in Lipidology, 26, 536–543. doi:10.1097/
health-topics/weight-control/bariatric-surgery/Pages/ MOL.0000000000000232
types.aspx Schwarz, S. M. (2016). Obesity in children. Retrieved from
Ochner, C. N., Tsai, A. G., Kushner, R. F., & Wadden, T. A. http://emedicine.medscape.com/article/
(2015). Treating obesity seriously: When 985333-overview
recommendations for lifestyle change confront
Unit 10
Pharmacology of the
Endocrine System
CHAPTER 64 Review of the Endocrine System / 1176
CHAPTER 65 Hypothalamic and Pituitary Drugs / 1183
CHAPTER 66 Pharmacotherapy of Diabetes Mellitus / 1200
CHAPTER 67 Pharmacotherapy of Thyroid Disorders / 1229
CHAPTER 68 Corticosteroids and Drugs Affecting the Adrenal Cortex / 1245
CHAPTER 69 Estrogens, Progestins, and Drugs Modifying Uterine Function / 1262
CHAPTER 70 Drugs for Modifying Conception / 1287
CHAPTER 71 Drugs for Disorders and Conditions of the Male
Reproductive System / 1307
1175
Chapter 64
Review of the Endocrine System
Chapter Outline Learning Outcomes
cc Overview of the Endocrine System After reading this chapter, the student should be able to:
cc Hormone Receptors
cc Negative Feedback Mechanisms 1. Describe the general structure and functions of the
cc Hormone Pharmacotherapy endocrine system.
2. Compare and contrast the nervous and endocrine
systems in the control of homeostasis.
3. Explain circumstances in which hormone receptors
may be up-regulated or down-regulated.
4. Through the use of a specific example, explain the
concept of negative feedback in the endocrine
system.
5. Explain the three primary types of stimuli that
regulate hormone secretion.
6. Identify indications for hormone pharmacotherapy.
1176
Chapter 64 Review of the Endocrine System 1177
Key Terms negative feedback, 1179 target cells, 1177
replacement therapy, 1180 up-regulation, 1177
down-regulation, 1177
endocrine system, 1177
hormones, 1177
Like the nervous system, the endocrine system is a major smooth muscle cells, they contract. When prolactin binds
controller of homeostasis. Whereas a nerve exerts instanta- to secretory cells in the breast, milk production occurs.
neous control over a single muscle fiber or gland, a hor-
mone from the endocrine system may affect all body cells Although a hormone travels throughout the body via
and take as long as several days to produce an optimal the circulation, it only affects cells that have receptors for
response. Hormonal balance is kept within a narrow range: that specific hormone. Epinephrine does not affect breast
Too little or too much of a hormone can produce profound secretory cells, because these cells have no epinephrine
physiologic changes. This chapter reviews endocrine anat- receptors. Prolactin does not cause muscular contraction
omy and physiology and its relevance to pharmacotherapy. because smooth muscle cells do not have prolactin recep-
For a more detailed review of the endocrine system, the stu- tors. This concept is illustrated in Figure 64.2.
dent should refer to an anatomy and physiology textbook.
In some cases, the target cells for a hormone are limited
Overview of the Endocrine System and specific. For example, the only receptors for thyroid-
stimulating hormone are in the thyroid gland. However,
64.1 The endocrine system controls homeostasis some hormones, such as insulin and cortisol, have recep-
through the secretion of hormones. tors on nearly every cell in the body; thus, these hormones
have widespread effects.
The endocrine system consists of glands that secrete hor-
mones, chemical messengers released in response to a The number of protein receptors for a hormone is
change in the body’s internal environment. The role of hor- dynamic and changes with the needs of the body. Cells can
mones is to maintain homeostasis in the body. For exam- create more receptors on their plasma membrane to cap-
ple, when the level of glucose in the blood rises above ture hormone molecules as they pass by, a process called
normal, the pancreas secretes insulin to return glucose lev- up-regulation. This may occur if the cell is receiving sig-
els to normal. The various endocrine glands and their hor- nals that a hormone action is needed, such as the need for
mones are illustrated in Figure 64.1. production of more breast milk or additional secretion of
thyroid hormone. Once the hormone is up-regulated
After secretion from an endocrine gland, hormones (secreted in large quantities), the cell no longer needs to
enter the blood and are transported throughout the body. capture every hormone molecule so it makes fewer recep-
Compared to the nervous system, which reacts to body tors on its surface, a process called down-regulation.
changes within milliseconds, the endocrine system responds Receptors are very efficient at capturing hormone mole-
relatively slowly. A few hormones, such as epinephrine, act cules; although most hormones are secreted only in small
within seconds, whereas others, such as testosterone, may amounts, they produce profound changes.
take several days or even months to produce noticeable
changes. Although slower in onset, the effects of hormones Down-regulation has important implications for phar-
have a longer duration than those of the nervous system. macotherapy. When a hormone is administered as pharma-
cotherapy for long periods, the body recognizes an
Hormone Receptors abundance of the hormone, and cells will down-regulate the
number of receptors for that hormone. This causes a desen-
64.2 Hormones must bind to specific receptors sitization of the target cells; that is, they are less responsive to
to cause physiologic changes. the effects of the hormone. When therapy is discontinued,
the cells will need time, usually several days, to synthesize
The cells affected by a hormone are called its target cells. more protein receptors and adjust to the new hormone level.
Target cells have specific protein receptors on their plasma
membrane that bind to the hormone. For some hormones, It is important to understand that the amount of hor-
the receptors are in the cytoplasm or nucleus of the target mone secreted by an endocrine gland is only partially
cell. Once binding occurs, a change is produced in the cell, responsible for the therapeutic response. Other critical
resulting in an action that is characteristic for the hormone. components include the number of receptors and their sen-
For example, when epinephrine binds to receptors on sitivity. During pharmacotherapy, increasing the dose of a
hormone will produce little additional pharmacologic
effect if all the receptors are already occupied, or if they are
no longer sensitive to the hormone.
1178 Unit 10 Pharmacology of the Endocrine System
HYPOTHALAMUS Direct release CRH Corticotropin-releasing hormone
of hormones GHIH Growth hormone-inhibiting hormone
PIH Prolactin-inhibiting hormone
Adrenocorticosteroids Indirect control through release of regulatory factors MSH-IH Melanocyte-stimulating hormone-
CRH TRH GHIH PIH GHRH
GnRH MSH-IH inhibiting hormone
GnRH Gonadotropin-releasing hormone
GHRH Growth hormone-releasing hormone
TRH Thyrotropin-releasing hormone
ACTH Adrenocorticotropic hormone
TSH Thyroid-stimulating hormone
GH Growth hormone
PRL Prolactin
FSH Follicle-stimulating hormone
LH Luteinizing hormone
MSH Melanocyte-stimulating hormone
ADH Antidiuretic hormone
Adrenal Anterior lobe Posterior lobe Kidneys
gland of pituitary of pituitary Uterine
ADH smooth
Thyroid ACTH muscle
gland Oxytocin Melanocytes
Thyroid TSH
hormones GH MSH
PRL
FSH LH
Peripheral Breast Testis Ovary
tissues Testosterone
Estrogen Progesterone
Figure 64.1 Hormones and the endocrine system.
PharmFACT Negative Feedback Mechanisms
Although it does not appear in most textbooks as an 64.3 Most hormone action is regulated through
endocrine organ, adipose tissue secretes hormones that negative feedback.
affect energy balance. Endocrine-disrupting chemicals, called
obesogens, have been discovered that alter normal adipose Because hormones can produce profound effects on the
tissue endocrine secretions and could possibly lead to obesity body, their secretion and release is carefully regulated by
(Janesick & Blumberg, 2016). several levels of control. The most important mechanism is
Chapter 64 Review of the Endocrine System 1179
Hormones and Target Cells
1. Endocrine cells
release hormone.
2. Hormone enters
circulation.
Hormone will not 3. Hormone is
bind to cells that carried through-
are not target cells out the body.
receptor 4. Binding occurs;
hormonal e ects
take place.
target cell
(skeletal muscle)
Figure 64.2 Hormones and their target cells.
From Biology: A Guide to the Natural World, 5th ed., by D. Krogh, 2011. Reprinted and electronically
reproduced by permission of Pearson Education, Inc., Upper Saddle River, New Jersey.
negative feedback, which is illustrated in Figure 64.3. A - Hypothalamus
hormone causes an output or action in its target cell or tis-
sue. As the level of a hormone rises, so does the hormone’s -+ Pituitary
action. The increased output or action is monitored by sen-
sors. Once homeostasis is restored, the sensor signals the Releasing
endocrine tissue to stop secreting the hormone; that is, the hormone
target tissue provides negative feedback.
Negative Pituitary hormone
Depending on the specific hormone, the negative feed- feedback +
back mechanism may be based on three primary types of
stimuli: neuronal, humoral, and hormonal. In some cases, Target tissue
regulation involves multiple stimuli. The various hor-
mones and their regulation are summarized in Table 64.1. Hormone from
target tissue
Neuronal stimuli: A few hormones are regulated by
nerve impulses. The best example is epinephrine, which is Figure 64.3 Negative feedback mechanism.
released when a neuronal impulse from the sympathetic
nervous system reaches the adrenal medulla. Another hormone. In some cases, the sequence involves three hor-
example is the release of oxytocin from the pituitary gland. mones. For example, thyrotropin-releasing hormone (TRH,
from the hypothalamus) stimulates thyroid-stimulating
Humoral stimuli: Some endocrine glands sense the levels hormone (TSH, from the pituitary), which causes the
of specific substances in the blood and release the hormone release of thyroid hormone (TH, from the thyroid gland).
when the substance rises above or falls below the normal
range. For example, pancreatic islet cells can sense the level
of glucose in the blood. If glucose levels become too high,
insulin is secreted. Another example is the release of para-
thyroid hormone when blood calcium levels fall.
Hormonal stimuli: In the endocrine system, it is com-
mon for one hormone to control the secretion of another
1180 Unit 10 Pharmacology of the Endocrine System
Table 64.1 Selected Hormones and Their Regulation
REGULATION
Hormone Target Organ(s) and Action Stimulation Inhibition
Adrenocorticotropic Corticotropin-releasing hormone Negative feedback from
hormone (ACTH) Adrenal cortex: stimulates release of corticosteroids
Aldosterone glucocorticoids Renin-angiotensin-aldosterone pathway, Increased blood volume or
decreased blood volume, hypotension hypertension
Antidiuretic Kidneys: promotes reabsorption of sodium and Increased osmolarity of blood or Adequate hydration
hormone (ADH) water decreased blood volume
Corticosteroids Adrenocorticotropic hormone (ACTH) Negative feedback from
(glucocorticoids) Kidneys: increases water reabsorption corticosteroids
Gonadotropin-releasing hormone
Follicle-stimulating Most tissues: increases protein breakdown and (GnRH) Negative feedback from estrogen
hormone (FSH) glucose metabolism, provides resistance to (women) or testosterone (men)
stress, suppresses inflammation and immune Growth hormone-releasing hormone
Growth response (GHRH) Negative feedback from GH or
hormone (GH) growth hormone-inhibiting hormone
Ovaries: promotes maturation of ovarian follicles Hyperglycemia (GHIH)
Insulin and estrogen production Hypoglycemia
Testes: increases sperm production Gonadotropin-releasing hormone
Luteinizing hormone (GnRH) Negative feedback from estrogen and
(LH) Most tissues, including bone, muscle, liver: progesterone (women) or
stimulates growth and mobilizes lipids Stretching of uterus or infant suckling testosterone (men)
Oxytocin Lack of stretching of the uterus or
Most tissues: promotes movement of glucose Hypocalcemia discontinuation of breastfeeding
Parathyroid into cells, lowers blood glucose, decreases Hypercalcemia
hormone glycogen synthesis, and increases lipogenesis Prolactin-releasing hormone
Prolactin and protein synthesis Thyroid-stimulating hormone Prolactin-inhibiting hormone
Thyroid hormone Negative feedback from thyroid
Ovaries: stimulates ovulation and production of hormone
estrogen
Testes: produces testosterone
Uterus: stimulates contractions
Breasts: ejects milk
Kidneys, gastrointestinal tract, bone: increases
calcium levels in blood
Breasts: promotes lactation
Most tissues: increases basal metabolic rate and
growth
In a loop typical of the endocrine system, the last hormone not functioning, or administering growth hormone to chil-
in the pathway (TH) provides negative feedback to shut dren with short-stature disorder. The pharmacologic goal
off secretion of the initial hormone (TRH). of replacement therapy is to supply the same physiologic,
low-level amounts of the hormone that would normally be
CONNECTION Checkpoint 64.1 present in the body. Selected endocrine disorders and their
drug therapy are summarized in Table 64.2.
From what you learned in Chapter 15, identify indications for epineph-
rine pharmacotherapy. Answers to Connection Checkpoint questions Some hormones are used in cancer chemotherapy to
are available on the faculty resources site. Please consult with your shrink the size of hormone-sensitive tumors. For exam-
instructor. ple, certain breast cancers are strongly dependent on
estrogen for their growth. Giving the “opposite” hor-
Hormone Pharmacotherapy mone, testosterone, will shrink the tumor. In a similar
manner, estrogen is used to shrink the size of testicular
64.4 Hormone pharmacotherapy is indicated for cancer, which is dependent on testosterone for its growth.
a diverse variety of conditions. Exactly how these hormones produce their antineoplastic
action is largely unknown. When hormones are used as
The goals of hormone pharmacotherapy vary widely. In antineoplastics, their doses far exceed physiologic levels
many cases, a hormone is administered as replacement normally present in the body. Hormones are nearly
therapy for patients who are unable to secrete sufficient always used in combination with other antineoplastic
quantities of their own endogenous hormones. Examples medications.
of replacement therapy include the administration of thy-
roid hormone after the thyroid gland has been surgically Another goal of hormonal pharmacotherapy may be
removed, supplying insulin to patients whose pancreas is to produce an exaggerated response that is part of the nor-
mal action of the hormone. Administering hydrocortisone
Chapter 64 Review of the Endocrine System 1181
Table 64.2 Selected Endocrine Disorders and Their Pharmacotherapy
Gland Hormone(s) Disorder Drug Therapy Examples
Adrenal cortex Corticosteroids Hypersecretion: Cushing’s syndrome ketoconazole (Nizoral) and mitotane (Lysodren)
Gonads Hyposecretion: Addison’s disease hydrocortisone, prednisone
Ovaries: estrogen Hyposecretion: menstrual and metabolic dysfunction conjugated estrogens and estradiol
Ovaries: progesterone Hyposecretion: dysfunctional uterine bleeding medroxyprogesterone (Provera, others) and
norethindrone
Pancreatic islets Testes: testosterone Hyposecretion: hypogonadism testosterone
Parathyroid Insulin Hyposecretion: diabetes mellitus insulin and oral antidiabetic drugs
Parathyroid hormone Hypersecretion: hyperparathyroidism surgery (no drug therapy)
Hyposecretion: hypoparathyroidism vitamin D and calcium supplements
Pituitary Antidiuretic hormone Hyposecretion: diabetes insipidus desmopressin (DDAVP, Stimate) and vasopressin
Hypersecretion: syndrome of inappropriate antidiuretic conivaptan (Vaprisol) and tolvaptan (Samsca)
Thyroid Growth hormone hormone (SIADH)
Hyposecretion: small stature somatropin (Genotropin, others)
Oxytocin Hypersecretion: acromegaly (adults) octreotide (Sandostatin)
Thyroid hormone Hyposecretion: delayed delivery or lack of milk ejection oxytocin (Pitocin)
(T3 and T4) Hypersecretion: Graves’ disease propylthiouracil (PTU) and 131I
Hyposecretion: myxedema (adults), cretinism (children) thyroid hormone and levothyroxine (T4)
to suppress inflammation takes advantage of the normal actions of endogenous hormones. For example, propylthio-
action of the corticosteroids but at higher amounts than uracil (PTU) is given to block the effects of an overactive
would normally be present in the body. Hydrocortisone is thyroid gland. Tamoxifen is given to block the actions of
indicated for acute inflammatory disorders such as lupus estrogen in estrogen receptor–dependent breast cancers
or rheumatoid arthritis. As another example, supplying (see Chapter 57).
estrogen or progesterone at specific times during the uter-
ine cycle can prevent ovulation and pregnancy. In this CONNECTION Checkpoint 64.2
example, the patient is given natural hormones; however,
they are taken at a time when levels in the body are nor- Glucocorticoids, or corticosteroids, are important drugs in treating
mally low. inflammation. From what you learned in Chapter 42, explain their role
in treating autoimmune disease. Answers to Connection Checkpoint
Endocrine pharmacotherapy also involves the use of questions are available on the faculty resources site. Please consult with
“antihormones.” These hormone antagonists block the your instructor.
Understanding Chapter 64
Key Concepts Summary 64.3 Most hormone action is regulated through negative
feedback.
64.1 The endocrine system controls homeostasis through
the secretion of hormones. 64.4 Hormone pharmacotherapy is indicated for a
diverse variety of conditions.
64.2 Hormones must bind to specific receptors to cause
physiologic changes.
References Krogh, D. (2011). Biology: A guide to the natural world
(5th ed.). Upper Saddle River, NJ: Pearson.
Janesick, A. S., & Blumberg, B. (2016). Obesogens: An
emerging threat to public health. American Journal of
Obstetrics & Gynecology, 214, 559–565. doi:10.1016/j.
ajog.2016.01.182
1182 Unit 10 Pharmacology of the Endocrine System Martini, F. H., Nath, J. L., & Bartholomew, E. F. (2015).
Fundamentals of human anatomy and physiology (10th ed.).
Selected Bibliography Hoboken, NJ: Pearson.
Chawla, J. (2016). Endocrine system anatomy. Retrieved Molina, P. (2014). Endocrine physiology (4th ed.). Blacklick,
from http://emedicine.medscape.com/article/ OH: McGraw Hill.
1948709-overview
Silverthorn, D. U. (2016). Human physiology: An integrated
Colbert, J. B., Ankney, J., & Lee, K. T. (2016). Anatomy and approach (7th ed.). Hoboken, NJ: Pearson.
physiology for health professionals: An interactive journey
(3rd ed.). Hoboken, NJ: Pearson.
Marieb, E., & Hoehn, K. (2016). Human anatomy and
physiology (10th ed.). Hoboken, NJ: Pearson.
“I’m really worried about Raj.
He’s always been small for his
age, and today the pediatrician
told me he is only at the
fifth percentile for height and
weight for his age. The doctor
is referring us to a pediatric
endocrinologist. Could it be
something serious?”
“Jasdeep Singh,” mother of 8-year-old patient “Raj”
Chapter 65
Hypothalamic and Pituitary Drugs
Chapter Outline Learning Outcomes
cc Functions of the Hypothalamus After reading this chapter, the student should be able to:
cc Functions of the Pituitary Gland
cc Pharmacotherapy of Growth Hormone Disorders 1. Explain the principal actions of the hormones
secreted by the hypothalamus and pituitary gland.
Growth Hormone Analogs
PROTOTYPE Somatropin (Genotropin, Humatrope, 2. Identify indications for hypothalamic hormone
Norditropin, Nutropin, Saizen, Serostim, therapy.
Zorbtive), p. 1188
Growth Hormone Antagonists 3. Explain the pharmacotherapy of growth hormone
PROTOTYPE Octreotide (Sandostatin), p. 1190 disorders in children and adults.
cc Pharmacotherapy of Antidiuretic Hormone
Disorders 4. Explain the pharmacotherapy of antidiuretic
PROTOTYPE Desmopressin (DDAVP, hormone disorders.
Noctiva, Stimate), p. 1194
5. For each of the classes shown in the chapter outline,
identify the prototype and representative drugs and
explain the mechanism(s) of drug action, primary
indications, contraindications, significant drug
interactions, pregnancy category, and important
adverse effects.
6. Apply the nursing process to the care of patients
receiving pharmacotherapy for disorders of the
hypothalamus and pituitary gland.
1183
1184 Unit 10 Pharmacology of the Endocrine System
Key Terms growth hormone (GH), 1186 syndrome of inappropriate
antidiuretic hormone
acromegaly, 1190 insulin-like growth (SIADH), 1194
anterior pituitary gland, 1185 factor (IGF), 1186
diabetes insipidus (DI), 1194 tropic hormones, 1185
dwarfism, 1186 posterior pituitary gland, 1185
gigantism, 1190
short stature, 1187
In the specialty of endocrinology, understanding the com- multiple and diverse functions of this organ include control
plex relationship between the hypothalamus and pituitary of body temperature, thirst, appetite, fatigue, circadian
gland is important because these organs regulate so many rhythms, anger, and the rate of overall body metabolism.
homeostatic functions. For example, the two organs col- The hypothalamus also controls vital functions of the auto-
laborate to secrete hormones that control functions of the nomic nervous system such as heart rate, vasoconstriction,
gonads, adrenal glands, thyroid gland, kidneys, and the digestion, and sweating. For the purposes of this chapter,
milk-producing tissues of the breast. The functioning of only the endocrine functions of the hypothalamus are
these two glands serves as the control center that provides presented.
integration between the nervous and endocrine systems.
This chapter examines drugs that directly affect the func- Every hormone has target cells that possess receptors for
tions of the hypothalamus and pituitary gland. that specific hormone. For the hormones secreted by the
hypothalamus, there is only one target organ: the pituitary
Functions of the Hypothalamus gland. All hypothalamic hormones travel by the blood a
short distance to the pituitary, which lies immediately below
65.1 The hypothalamus controls many diverse the hypothalamus. Upon reaching their receptors, the hypo-
body processes and secretes hormones that thalamic hormones simply increase or decrease the release of
influence pituitary function. hormones by the pituitary gland. Because of this, hormones
from the hypothalamus are called releasing hormones or
Roughly the size of an almond, the hypothalamus lies in inhibiting hormones. The major hypothalamic hormones and
the center of the diencephalon of the brain, just superior to their actions on the pituitary gland are given in Table 65.1.
the brainstem. The general purpose of the hypothalamus is
to maintain homeostasis. To achieve this, the hypothalamus There are very few indications for the administration
receives input from numerous vital regions of the nervous of hypothalamic hormones. Rather than give hypothalamic
system, recognizes imbalances, and makes adjustments to hormones, it is more effective (and less expensive) to
bring the body back to homeostasis. Examples of the administer pituitary hormones or the secretions of a target
endocrine organ such as thyroid hormone, estrogen, testos-
terone, or corticosteroids.
Table 65.1 Hormones Secreted by the Hypothalamus and Pituitary Glands
Hypothalamic Hormone Pituitary Hormone Target Organ Principal Actions
Stimulates release of corticosteroids
Corticotropin-releasing hormone (CRH) Adrenocorticotropic hormone (ACTH) Adrenal cortex Stimulates release of estrogen and ovarian follicle
Follicle-stimulating hormone (FSH) Ovaries, testes development in women, and sperm production in men
Gonadotropin-releasing hormone Triggers ovulation and secretion of estrogen and
(GnRH) Luteinizing hormone (LH) Ovaries, testes progesterone in women, increases testosterone
secretion in men
Growth hormone-inhibiting hormone Growth hormone (GH) Most body cells Regulates growth and development of bones, muscles,
(GHIH) cartilage, organs; general body metabolism
Growth hormone-releasing hormone Melanocyte-stimulating hormone Skin
(GHRH) (MSH) Mammary Stimulates pigmentation
None Prolactin glands
Thyroid-stimulating hormone (TSH) Thyroid gland Regulates lactation
Prolactin-inhibiting hormone (PIH)
Prolactin-releasing hormone (PRH) Stimulates release of thyroid hormone
Thyrotropin-releasing hormone (TRH)
Table 65.2 Hypothalamic Medications Chapter 65 Hypothalamic and Pituitary Drugs 1185
Drug Action Indication
Female infertility
cetrorelix (Cetrotide) GnRH antagonist Advanced prostate cancer
degarelix (Firmagon) GnRH antagonist Female infertility
ganirelix GnRH antagonist Men: Stage 2 prostate cancer and palliation of advanced prostate
goserelin (Zoladex) GnRH analog cancer
Palliation of advanced prostate cancer (Vantas) and treatment of
histrelin (Supprelin LA, Vantas) GnRH analog precocious puberty (Supprelin LA)
Men (Eligard, Viadur): palliation of advanced prostate cancer
leuprolide (Eligard, Lupron, Viadur) GnRH analog Women (Lupron): endometriosis and leiomyomata
Precocious puberty
nafarelin (Synarel) GnRH analog Palliation of advanced prostate cancer
triptorelin (Trelstar) GnRH analog
The hypothalamic hormones that do have clinical from the hypothalamus is usually to enhance the release of
applications are analogs or antagonists of gonadotropin- hormones, as is the case for growth hormone-releasing hor-
releasing hormone (GnRH). Initially the effect of the GnRH mone (GHRH), thyrotropin-releasing hormone (TRH),
analogs is to increase the production of interstitial cell- prolactin-releasing hormone (PRH), corticotropin-releasing
stimulating hormone (in men) or follicle-stimulating hor- hormone (CRH), and gonadotropin-releasing hormone
mone (in women), which increases the secretion of sex (GnRH). Two of the hypothalamic secretions, growth hor-
hormones. With continued therapy, however, the pituitary mone-inhibiting hormone (GHIH) and prolactin-inhibiting
becomes insensitive to the effects of GnRH, and the produc- hormone (PIH), prevent the release of pituitary hormones.
tion of sex hormones falls to near castration levels. Indica-
tions for these drugs are shown in Table 65.2. Doses and The posterior pituitary gland (neurohypophysis), by
additional information may be found in Chapters 57 and 69. contrast, consists of nervous tissue and is basically an
extension of the hypothalamus. It secretes two hormones:
CONNECTION Checkpoint 65.1 antidiuretic hormone (ADH) and oxytocin. These hor-
mones are manufactured in the hypothalamus and travel
Target tissues can up-regulate or down-regulate the number of recep- down neurons to the posterior pituitary where they are
tors for a specific hormone. From what you learned in Chapter 64, stored until factors stimulate their release. The primary
which of the two processes occurs when a hormone is administered stimulus causing ADH secretion is an increased serum
as pharmacotherapy for long periods? Answers to Connection Check- osmolality, or a high concentration of solutes in the blood.
point questions are available on the faculty resources site. Please consult Oxytocin release is stimulated by touch receptors in the
with your instructor. nipples of lactating women. Pharmacotherapy with oxyto-
cin is presented in Chapter 69.
Functions of the Pituitary Gland
Regulation of hormone levels is an essential function
65.2 The pituitary gland secretes hormones that because too little or too much of any of these endocrine
control many diverse body functions. secretions can cause profound symptoms. Many are con-
trolled by negative feedback loops. As circulating levels of
Although the pituitary gland is often referred to as the a hormone rise above normal, a message is sent to the
“master gland,” its function is largely controlled by releas- hypothalamus, pituitary, or other endocrine gland to shut
ing or inhibiting hormones from the hypothalamus. The down the manufacture and secretion of the hormone. This
pituitary gland is divided into anterior and posterior lobes, prevents excess hormone levels. When hormones are
which have very different structures and functions. administered as drug therapy, they can influence this nor-
mal negative feedback mechanism. One of the most impor-
The anterior pituitary gland (adenohypophysis) com- tant examples of this phenomenon is the negative feedback
prises glandular tissue that manufactures and secretes hor- suppression of the adrenal glands caused by administra-
mones that control major body functions and systems. Four tion of corticosteroid medications. The student should
of these are called tropic hormones, a term that refers to the review the information on negative feedback in Chapter 64
ability of these hormones to regulate the secretory actions before proceeding.
of other endocrine glands. The anterior pituitary hormones
are synthesized and stored in the pituitary until they Because of the widespread effects of the hormones
receive a message from the hypothalamus. The message secreted and controlled by the hypothalamus and pituitary
glands, disorders of these glands are quite complex. In
1186 Unit 10 Pharmacology of the Endocrine System
general, the pathologies of endocrine glands can be catego- )*4* )*+* *[RQVJCNCOWU
rized as causing hypofunction or hyperfunction of the par-
ticular gland. Pituitary disorders can be the result of tumors, 12
surgery, radiation therapy, infection, injury, infarction (loss
of blood supply), or bleeding (hemorrhage) in the area. )TQYVJ 2KVWKVCT[
Congenital defects may also result in absent or impaired JQTOQPG
function of a hormone, or the lack of an enzyme necessary
for hormone production.
Pharmacotherapy of Growth +PFKTGEV &KTGEV GHHGEVU
Hormone Disorders GHHGEVU +)(
65.3 Growth hormone deficiency in adults .KXGT
and children can be treated by administering
recombinant growth hormone. +PETGCUGF DNQQF
INWEQUG NGXGNU
Growth hormone (GH), also called somatotropin or soma-
tropin, is produced and secreted by the anterior pituitary +PETGCUGF DQPG .KRQN[UKU CPF +PETGCUGF
gland. This hormone was once believed to be of impor- CPF TGNGCUG QH HCVV[ CEKFU UMGNGVCN OWUENG
tance only during periods of active growth, but it is now HTQO CFKRQUG VKUUWG
recognized that adults produce nearly as much GH as chil- ECTVKNCIG ITQYVJ OCUU
dren. Although its major targets are bone and skeletal
muscle, GH stimulates many types of body cells to increase Figure 65.1 Physiologic and pharmacologic effects of growth
in size and replicate. It is considered an anabolic (tissue- hormone.
building) hormone. The primary effects of GH, illustrated
in Figure 65.1, are as follows: Table 65.3 Selected Factors Affecting the Release
• Increases length and width of bone of Growth Hormone
• Stimulates cartilage growth
• Stimulates the growth and development of most vis- Factors Increasing Factors Decreasing
Release of GH Release of GH
ceral and endocrine organs, skeletal and cardiac mus-
cle, and skin and connective tissue Amino acids: leucine, arginine Beta-adrenergic agonists
• Enhances cellular uptake of amino acids and increased Androgens and estrogens Carbohydrate-rich diet
protein synthesis Clonidine Cortisol
• Breaks down adipose tissue to release fatty acids for Elevated body temperature Free fatty acids
use as fuel Gamma-hydroxybutyrate Increased serum glucose level
• Decreases use of glucose; impairs glucose tolerance Growth hormone-releasing Obesity
and induces insulin resistance in peripheral tissues. hormone (GHRH) Somatostatin (GHIH)
Hypoglycemia, fasting, starvation
Many of the effects of GH are dependent on insulin- L-dopa
like growth factor (IGF), a family of peptides that promote Stress, trauma
cartilage and bone growth. IGFs are produced in the liver Vigorous exercise
and are released when hepatic cells become activated by
GH. Secretion of GH fluctuates during the day, peaking 1 to
4 hours following the onset of sleep. These nighttime bursts
in GH are greater in children than in adults.
The overall regulation of serum GH levels resides in
the hypothalamus, with the secretion of GHRH and GHIH.
A large number of secondary factors, such as exercise and
sleep, influence the release of GH, and these are listed in
Table 65.3.
In children, GH deficiency results in dwarfism. Dwarf-
ism is associated with normal birth length followed by a
slowing of the growth rate. These children have normal
intelligence, short stature, immature facial features, obesity,
Chapter 65 Hypothalamic and Pituitary Drugs 1187
and delayed skeletal maturation. In this context, short stat- called somatropin. Doses for the GH analogs are listed in
ure is defined as well below the fifth percentile for age and Table 65.4.
gender, or more than two standard deviations below the
mean (average) height for age and gender. Acquired GH Therapy with recombinant GH is expensive, with a
deficiency develops later in childhood and can be caused cost of approximately $50,000 per inch of growth. The hor-
by a hypothalamic-pituitary tumor or an infection. Chil- mone is administered subcutaneously, several times a week
dren who have been severely neglected or emotionally during the period of active growth, and therapy may con-
deprived can develop a psychosocial dwarfism, with poor tinue until adulthood. Females with Turner’s syndrome
growth, a potbelly, and poor nutritional habits. GH levels and children with chronic kidney disease (CKD) may also
often return to normal once the child is removed from the be treated with GH. Often, treatment with GH produces
dysfunctional environment. only modest gains in final adult height, but these gains are
considered beneficial to the psychologic well-being of the
When GH deficiency is the cause of short stature, patient.
replacement therapy is the preferred treatment. Until 1985,
GH was obtained from the pituitary glands of human Adult GH deficiency is associated with reduced mus-
cadavers, a practice that was halted following the deaths of cle mass, increased cardiovascular mortality, central adi-
several recipients who developed Creutzfeldt–Jakob dis- posity and increased visceral fat, insulin resistance, and
ease. GH is now obtained using recombinant DNA technol- dyslipidemia. This hormonal deficiency may develop dur-
ogy. GH obtained through recombinant technology is ing adulthood, or it may be a continuation of childhood
deficiency. Several forms of recombinant human GH
Table 65.4 Drugs Acting on the Pituitary Gland and Target Tissues
Drug Route and Adult Dose Adverse Effects
bromocriptine (Cycloset, (Maximum Dose Where Indicated) Orthostatic hypotension, nausea, vomiting, fatigue, dizziness,
Parlodel) headache
PO (Cycloset): 0.8 mg daily, increased weekly to achieve Shock, acute MI, cerebral ischemia, confusion, agitation, psychosis
desmopressin (DDAVP, 1.6–4.8 mg daily
Noctiva, Stimate) PO: 1.25–2.5 mg/day for 3 days, then increase dose every Headache, nasal congestion or irritation, nausea
3–7 days to 30–60 mg/day Water intoxication, coma, thromboembolic disorder, hyponatremia
lanreotide (Somatuline
Depot) IV/subcutaneous: 2–4 mcg in 2 divided doses Pain at the injection site, nausea, vomiting, diarrhea, itching
mecasermin (Increlex) PO: 0.2–0.4 mg/day Gallstones, abdominal pain, bradycardia, hyper- or hypoglycemia
Intranasal: 1 spray in either right or left nostril 30 min Injection-site reaction, iron deficiency anemia, goiter, antibody
octreotide (Sandostatin) before bedtime development, headache, hypertrophy of tonsils
Hypoglycemia, increased intracranial pressure
Subcutaneous: 60–120 mg q4wk Nausea, vomiting, diarrhea, headache, flushing, injection-site pain,
cholelithiasis
Subcutaneous: 0.04–0.08 mg/kg bid. Must be
administered within 20 min of a meal or snack
(max: 0.12 mg/kg bid)
Subcutaneous/IV: 100–600 mcg/day in 2–4 divided
doses; after 2 wk may switch to IM depot, 20 mg q4wk
pasireotide (Signifor IM: 40 mg once q4wk Dysrhythmia, worsening heart failure, sinus bradycardia
LAR)
Diarrhea, cholelithiasis, hyperglycemia, QT prolongation,
bradycardia
pegvisomant (Somavert) Subcutaneous: 40 mg loading dose, then 10 mg/day Diabetes
(max: 30 mg/day) Nausea, diarrhea, injection-site pain, flulike symptoms
Liver damage, elevated transaminase levels
somatropin (Genotropin, Subcutaneous (Humatrope): 0.006 mg/kg daily Pain at injection site, hyperglycemia, arthralgia, myalgia, abdominal
Humatrope, Norditropin, (max: 0.0125 mg/kg/day) pain, otitis media, headache, bronchitis, hypothyroidism, HTN,
Nutropin, Saizen, flulike symptoms
Serostim, Zorbtive) Subcutaneous (Serostim): Weight more than 55 kg: 6 mg Severe respiratory impairment in patients with severe obesity and
at bedtime; 45–55 kg: 5 mg at bedtime; 35–45 kg: 4 mg Prader-Willi syndrome, diabetes, pancreatitis, scoliosis of the spine,
vasopressin at bedtime; less than 35 kg: 0.1 mg/kg at bedtime papilledema, intracranial tumor
Child: Tremor, pallor, nausea, vomiting, water retention, intoxication
Angina, acute MI, gangrene, anaphylaxis, cardiac arrest
Subcutaneous (Genotropin): 0.16–0.24 mg/kg/wk
in 6–7 divided doses
Norditropin: 0.024–0.034 mg/kg 6–7 times/wk
IM/subcutaneous: 5–10 units aqueous solution
2–4 times/day
IV: 0.2–0.4 units/min up to 1 unit/min
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
1188 Unit 10 Pharmacology of the Endocrine System
formulations (Humatrope and Genotropin) have been • Acquired immunodeficiency syndrome (AIDS) wast-
approved for use in adults with body-wasting–type disor- ing, cachexia, and severe thermal injuries (Serostim)
ders. Treatment can result in increased lean body mass,
decreased fat mass, increased bone mineral density, and • Short bowel syndrome in patients receiving special-
decreased lipid levels. ized nutrition support (Zorbtive).
Human GH has been abused for its anabolic effects. Although the various brand-name products of GH
Athletes have used the drug to build muscle, increase have the same effectiveness, they differ in potency and are
strength, and maintain less body fat. It has also been called not interchangeable. Some are available in prefilled
an antiaging drug because it promotes younger looking syringes, whereas others are longer acting. The nurse
skin, improved memory, and reduced wrinkles. The admin- should check the package insert for specific dosing
istration of GH for these purposes is illegal, and prolonged instructions.
use may lead to long-term adverse effects in patients.
Despite potential adverse health effects, products adver- Mechanism of Action: Somatropin has the same
tised as “human growth hormone supplements” are read- amino acid sequence as endogenous human GH and pro-
ily marketed without a prescription. These do not contain duces the same effects as the naturally occurring form of
any GH (which must be administered parenterally) but the hormone. The effects of GH are mediated by IGF.
instead contain a mixture of oral (PO) supplements that are
claimed to stimulate the pituitary gland. The safety and Pharmacokinetics: Subcutaneous, IM
effectiveness of these products have not been evaluated Route(s)
adequately. Absorption Well absorbed following
Distribution injection
PROTOTYPE DRUG Somatropin (Genotropin,
Humatrope, Norditropin, Nutropin, Primary metabolism Distributed to highly per-
Saizen, Serostim, Zorbtive) Primary excretion fused organs (liver, kidneys);
Onset of action circulates bound to GH
Classification Therapeutic: Human growth hormone Duration of action binding protein
Pharmacologic: Pituitary hormone
Hepatic; some metabolism in
Therapeutic Effects and Uses: Approved by the kidneys
U.S. Food and Drug Administration (FDA) in 1987, soma-
tropin is prepared through recombinant DNA technology Renal
and is identical to endogenous human GH. It is available
in several different formulations that vary by dose and Peak action variable: days to
regimen. The preferred route of administration is subcu- weeks
taneous, although some forms may be given via the intra-
muscular (IM) route. GH produces growth of long bones Half-life: 3.8–5 h
in children prior to epiphyseal closure. The gain in growth
is very rapid at the initiation of therapy but slows over Adverse Effects: Adverse effects of somatropin
time. Treatment may continue until the desired height is include hyperglycemia and insulin resistance, which is
achieved, epiphyseal closure occurs, or the patient fails made worse in patients with preexisting diabetes mellitus.
to respond to treatment. If treatment does not result in It can also cause hypothyroidism. Edema of the hands and
growth, it is stopped, and the diagnosis is reevaluated. feet, headache, and hypertension (HTN) often occur ini-
The metabolic effects of the drug include increased protein tially but may resolve with continued therapy. Joint pain,
synthesis, reduced carbohydrate utilization, and increased muscle aches, and pain at the injection site are common.
use of fatty acids for energy. Carpal tunnel syndrome may occur with use of Seros-
tim. Development of antibodies to GH may rarely occur.
GH is used in the management of a number of growth- Hypercalciuria, possibly asymptomatic, may occur in the
related disorders, including the following: first few months of therapy.
• Growth failure in children due to GH deficiency or Contraindications/Precautions: Somatropin is con-
Prader-Willi syndrome traindicated for use in patients with closed epiphyses. It
is also contraindicated in patients with severe obesity,
• Growth failure in children due to CKD (Nutropin) respiratory impairment, or sleep apnea due to potentially
• Short stature associated with Turner ’s syndrome fatal respiratory impairment. Somatropin should not be
used in patients with intracranial tumor due to the risk
(Genotropin, Humatrope, Norditropin, Nutropin) for increased growth or recurrence of tumor. The drug
• Adult GH deficiency (Genotropin, Humatrope, Nor- is contraindicated in patients who are sensitive to glyc-
erin. Somatropin should be used with caution in patients
ditropin, Nutropin, Saizen) with severe renal or hepatic disease due to reduced
clearance, and in patients with diabetes mellitus due to
Chapter 65 Hypothalamic and Pituitary Drugs 1189
hyperglycemia and insulin resistance. It should be used Drugs Similar to Somatropin (Genotropin,
with caution in pregnant or lactating patients because
safety has not been established. Humatrope, Norditropin, Nutropin, Saizen,
Drug Interactions: Corticosteroids interfere with the Serostim, Zorbtive)
bone growth–promoting action of GH; thus, the two should
not be given concurrently. Concurrent use with anabolic Mecasermin is the only other drug that has actions similar
steroids, androgens, estrogens, or thyroid hormone may to GH.
increase the rate of epiphyseal closure. Patients receiving
insulin should be monitored carefully because somatropin Mecasermin (Increlex): Approved in 2005, mecasermin
decreases the actions of insulin. Herbal/Food: Unknown. is a solution of IGF produced through recombinant DNA
technology. This drug is identical to endogenous IGF and
Pregnancy: Category B or C, depending on the specific therefore has the same actions as GH. Mecasermin is
formulation. indicated for two specific indications: the long-term
treatment of growth failure in children with severe pri-
Treatment of Overdose: Overdose with somatropin mary IGF deficiency, or for those who have developed
has not been reported. neutralizing antibodies to GH. It is not intended to be
used for any other forms of GH deficiency. It should not
Nursing Responsibilities: Key nursing implications be used in adults after the epiphyses have closed.
for patients receiving somatropin are included in the Nurs- Adverse effects include hypoglycemia, local and sys-
ing Practice Application for Patients Receiving Pharmaco- temic hypersensitivity, and tonsillar hypertrophy. Rare
therapy with Growth Hormone. adverse effects include intracranial HTN, slipped capital
epiphysis, and progression of scoliosis. Mecasermin use
should be monitored carefully in patients taking insulin
CONNECTIONS: Preparing for Advanced Practice
Traumatic Brain Injury and Hormones
Case Discussion
Emma was a 17-year-old promising young soccer player. Traumatic brain injury (TBI) is a form of acquired brain injury that
During her junior year in high school she spent weekends occurs when a sudden trauma causes damage to the brain. In
traveling to soccer tournaments, and she was being recruited Emma’s case, it occurred after a soccer ball hit her in the head.
by colleges around the country. Emma was being seen for Symptoms of a TBI can be mild, moderate, or severe, depend-
her annual sports physical examination. Her only concerns ing on the extent of damage to the brain. When minor head inju-
were her lack of height and that she often felt tired. At ries occur back to back it can cause compounding effects.
1.5 meters (5 ft 1 in.) she had not grown since she was Young athletes have been found to be both more susceptible to
12 years old. Her family history showed that her father was concussions than older athletes and more likely to get these
nearly 1.8 meters (6 feet) tall, her mother was 1.7 meters (5 ft compounding effects (Rose, Weber, Collen, & Heyer, 2015).
10 in.), and both sets of grandparents were above average
height. Emma did not smoke or drink alcohol, and denied Research has shown that TBI, even when mild, can have a
using any illicit drugs. She had a history of three mild head negative effect on pituitary function, which can cause low levels of
injuries that she acquired while playing soccer. In fact, she several hormones (Lauzier et al., 2014). Problems that can occur
was diagnosed twice with mild concussions 3 months apart soon after a head injury or be delayed include the following:
when she was 12 years old. On physical examination, she
displayed minimal breast tissue growth and was only at • Adrenal insufficiency occurs when the adrenal glands do not
Tanner stage III. Other than the slow development, her physi- make enough hormones. Symptoms include weight loss,
cal examination was unremarkable. As a result of the history fatigue, vomiting, dehydration, and low blood pressure.
of head injuries and her small stature and unusual growth Adrenal insufficiency can be life threatening if not treated.
pattern, blood testing for hormone levels was done. The
results showed that Emma had GH deficiency, adrenal insuf- • Diabetes insipidus occurs when the pituitary does not make
ficiency, and hypothyroidism. enough antidiuretic hormone (ADH). Symptoms include fre-
quent urination and extreme thirst.
Emma was started on growth hormone, cortisol, and
replacement thyroid hormone, and on her annual sports physi- • Hypothyroidism results when the levels of thyroid hormone
cal examination 1 year later she had grown an additional 8.9 cm in the body are insufficient. Symptoms include fatigue, con-
(3.5 in.). She feels less tired and is excited to have been offered stipation, weight gain, irregular menstrual periods, and cold
the opportunity to play soccer at the local university. Is Emma’s intolerance.
case unusual at such a young age?
• Growth hormone deficiency occurs when the body’s level of
growth hormone is insufficient. In adults, this leads to
increased fat, loss of muscle and bone, and decreased
energy; in children, growth problems and small stature.
1190 Unit 10 Pharmacology of the Endocrine System
or oral antidiabetic drugs because mecasermin can has resulted in its use in treating multiple secretory and
increase the actions of these medications. This drug is bleeding conditions of the intestinal tract. Because it stimu-
pregnancy category C. lates the absorption of fluid and electrolytes from the GI
tract and prolongs intestinal transit time, it is approved to
65.4 Overproduction of growth hormone in treat severe diarrhea and flushing episodes associated with
adults can be treated by administering growth metastatic carcinoid tumors or vasoactive intestinal pep-
hormone antagonists. tide tumors. Octreotide inhibits enzymes that cause vaso-
dilation, decreases hepatic and GI blood flow, and reduces
Excessive GH secretion that occurs prior to puberty and hepatic-portal venous pressure. These properties make the
the sealing of epiphyseal plates of the long bones results in drug useful in treating portal HTN and upper GI bleeding
gigantism, or unusual tallness. Gigantism is rare due to caused by esophageal varices. It is also used off-label to
early recognition of the cause of the oversecretion: a benign reduce the output from pancreatic and other GI fistulas.
pituitary adenoma. GH excess in children is usually treated
with surgery as soon as the disorder is diagnosed. Mechanism of Action: Octreotide produces the same
effects as the natural hormone somatostatin to suppress
Excessive GH secretion in adults causes a condition secretion of GH. It also suppresses secretion of serotonin,
known as acromegaly. Excess levels of GH stimulate the pancreatic peptides, gastrin, vasoactive intestinal peptides,
secretion of IGFs from the liver, which then produce the secretin, motilin, insulin, and glucagon.
clinical manifestations of the disorder. Because the epiphy-
seal plates are closed in adults, bones become deformed Pharmacokinetics:
rather than elongated with this disorder. The onset is grad-
ual, with enlargement of the bones of the hands, feet, face, Route(s) Subcutaneous or IM (depot
and skull, a broad nose, protruding lower jaw, and slanting
forehead. The cartilage of the larynx enlarges, deepening formulation)
the voice. Spinal changes can lead to kyphosis. Arthralgias
and degenerative arthritis may occur, and enlargement of Absorption Absorbed rapidly following
organs, including the heart, can result in an early death due
to atherosclerosis. Metabolic changes lead to insulin resis- subcutaneous injection
tance and impaired glucose tolerance. Treatment may con-
sist of a combination of surgery, radiation therapy, and Distribution May cross the placenta; may
pharmacotherapy to suppress GH secretion and correct
metabolic abnormalities. Doses of the GH antagonists are be secreted in breast milk; 65%
listed in Table 65.4.
bound to lipoproteins
PROTOTYPE DRUG Octreotide (Sandostatin)
Primary metabolism Liver
Classification Therapeutic: Growth hormone antago-
nist; antidiarrheal Primary excretion Renal
Pharmacologic: Somatostatin Onset of action 15–30 min (subcutaneous);
Therapeutic Effects and Uses: Approved in 1988, 60 min (IM)
octreotide, which is also called somatostatin, is a long-
acting peptide that mimics the actions of GHIH. Octreotide Duration of action 12 h; half-life: 1.5 h
is effective in both children and adults with GH excess. To
treat acromegaly, the drug is initially given 3 times daily Adverse Effects: The most common adverse effects
by the subcutaneous route. A long-acting IM form (Sand- of octreotide are related to the GI system: nausea, vomit-
ostatin LAR Depot) is available that reduces dosing to ing, diarrhea, abdominal discomfort, development of gall-
every 4 weeks. stones, and elevated liver enzymes. The nausea, vomiting,
and abdominal pain diminish with continued therapy. It
Although GHIH is primarily secreted by the hypothal- can also cause headache, fatigue, flushing, and edema.
amus, small amounts are also secreted by the stomach, Because hypoglycemia or hyperglycemia can develop with
intestine, and pancreas. Thus, in addition to its effect of long-term use, an adjustment in insulin doses in patients
blocking GH secretion in the anterior pituitary, octreotide with diabetes may be necessary. It can also cause cardiac
suppresses the release of multiple gastrointestinal (GI) hor- dysrhythmias, heart failure, and chest pain. Pain at the
mones, including gastrin, cholecystokinin (CCK), secretin, injection site is very common.
vasoactive intestinal peptide, insulin, and glucagon. This
Contraindications/Precautions: Octreotide is con-
traindicated in patients who are sensitive to it. It is used
with caution in patients with CKD, liver disease, cardiac
disease, diabetes, and hypothyroidism. Because the drug
can cause cholelithiasis, biliary obstruction, or cholecysti-
tis, it should be used cautiously in patients with preexist-
ing gallbladder disease. In addition, it is used with caution
in older adult patients due to a significantly longer half-life
and delayed clearance; dose adjustments are necessary for
these patients.
Chapter 65 Hypothalamic and Pituitary Drugs 1191
Drug Interactions: Octreotide may decrease cyclospo- • Reconstitute the drug gently, and avoid shaking the
rine levels and may alter the absorption of other drugs and vial to prevent damaging the drug. Allow the solution
nutrients because it slows intestinal motility. Concurrent to come to room temperature prior to injecting and
administration of octreotide with PO antidiabetic drugs or refrigerate any unused solution. Discard any discol-
insulin can produce hypoglycemia. Additive bradycardia ored solution or if particulate matter is present.
may occur when administered with cardiac drugs such as
beta blockers and calcium channel blockers. Concurrent • Immediately report to the healthcare provider any yel-
use of octreotide with antidiarrheals and opioids can lead lowing of skin or the whites of the eyes, sharp right
to severe constipation, intestinal obstruction, or paralytic upper abdomen pain, nausea, or vomiting, because
ileus. Herbal/Food: Octreotide decreases the absorption of these may indicate the development of liver or gall-
dietary fat and vitamin B12. bladder disease.
Pregnancy: Category B. • Report changes in bowel habits, either diarrhea or
constipation, or abdominal pain that is severe or that
Treatment of Overdose: Overdose with octreotide lasts more than 2 days.
has not been reported.
• Be aware that treatment is expensive, and therapy
Nursing Responsibilities: may be prolonged.
• Assess baseline height and weight and monitor regu- • Immediately notify the healthcare provider of any
larly to determine drug effectiveness. known or suspected pregnancy.
• Assess baseline and periodic electrocardiograms • Do not breastfeed during drug therapy without
(ECGs) because the drug may cause bradycardia and approval of the healthcare provider.
other dysrhythmias.
Drugs Similar to Octreotide (Sandostatin)
• Assess baseline and periodic vitamin B12 levels
because the drug can reduce the absorption of this Drugs with similar actions to octreotide include bro-
vitamin. Recommend supplementation as needed. mocriptine, lanreotide, pasireotide, and pegvisomant.
• Assess baseline and periodic hepatic and biliary func- Bromocriptine (Cycloset, Parlodel): Approved in 1978,
tion tests because this drug may cause or aggravate bromocriptine is a PO drug that is classified as a dopamine
existing gallbladder disease. agonist. Dopamine itself is not used for acromegaly due to
an unacceptable incidence of adverse effects. Bromocrip-
• Administer octreotide by subcutaneous injection as tine inhibits the secretion of GH as well as prolactin from
the preferred route, alternating among the recom- the pituitary. It is primarily indicated for Parkinson’s dis-
mended sites between the abdomen, thigh, and but- ease and infertility caused by prolactin excess, but it has
tock. Allow the solution to reach room temperature been used in combination with octreotide in children with
before administering. GH excess. In 2009, the FDA approved bromocriptine
(Cycloset) as an adjunct to diet and exercise to improve
• Monitor serum glucose levels frequently because this glycemic control in adults with type 2 diabetes mellitus.
drug can cause hypoglycemia and may require adjust-
ments in insulin dose. The most common dose-limiting adverse effects are
psychologic reactions including confusion, agitation, hal-
• Monitor the patient’s cardiac status, thyroid function, lucinations, paranoid delusions, or nightmares. Other
and electrolyte balance. adverse effects include orthostatic hypotension, head-
ache, nausea, vomiting, anorexia, or rash on the face and
Lifespan and Diversity Considerations: arms. Bromocriptine interferes with lactation and should
not be used during breastfeeding. It is a pregnancy cate-
• Monitor all laboratory studies and other diagnostic gory B drug.
testing more frequently in the older adult because nor-
mal physiologic changes related to aging may increase Lanreotide (Somatuline Depot): Approved in 2007, lan-
the risk of adverse effects. reotide is a somatostatin analog indicated for the treatment
of patients with acromegaly who have not responded to
• Because genetic, individual variations may affect the radiation therapy or who are unable to undergo surgical
results of drug therapy, monitor ethnically diverse treatment. The drug lowers levels of GH, thus improving
populations more frequently to ensure optimal thera- symptoms related to acromegaly. Lanreotide is a depot for-
peutic effects and minimize adverse effects. mulation that requires dosing only once per month. It is
available in prefilled syringes and is delivered by deep sub-
Patient and Family Education: cutaneous injection. Adverse effects associated with lanreo-
tide include pain at the injection site, nausea and vomiting,
• Administer the drug between meals and at bedtime to
minimize adverse GI effects. Rotate injection sites, and
use the preferred sites for injections: the abdomen,
thigh, or buttock.
1192 Unit 10 Pharmacology of the Endocrine System
diarrhea, gallstones, skin reactions such as itching, brady- Pegvisomant (Somavert): Approved in 1997, pegviso-
cardia, and changes in blood glucose levels (either hyper- mant is a specific GH receptor antagonist, making it very
or hypoglycemia). This drug is pregnancy category C. effective for acromegaly. The drug is structurally very
similar to GH, although when it binds to GH receptors, it
Pasireotide (Signifor LAR): Pasireotide is a somatostatin causes no cellular response. The multiple polyethylene
analog given once monthly by IM injection. The drug was glycol (PEG) molecules attached to the drug prolong its
approved in 2012 for Cushing’s disease, which is caused by half-life and allow for once-daily dosing. It is adminis-
a tumor of the adrenal gland that secretes excess adrenocor- tered subcutaneously once daily and is supplied as a pow-
ticotropic hormone (ACTH). Its indications were extended der for reconstitution. Adverse effects include nausea,
in 2014 for acromegaly in patients for which surgical treat- vomiting, elevated liver enzymes, angina, chest pain and
ment is not an option. The formulation for Cushing’s dis- myocardial infarction (MI), HTN, flulike syndrome, and
ease (Signifor) is not interchangeable with that for injection-site pain. Patients with diabetes should be moni-
acromegaly (Signifor LAR). The most common side effects tored regularly to avoid hypoglycemia. Therapy for this
are diarrhea and cholelithiasis. Hyperglycemia and diabetes drug is expensive and is continued indefinitely. It is a
may become severe during therapy. Pasireotide also pro- pregnancy category B drug.
longs the QT interval. This drug is pregnancy category C.
CONNECTIONS: NURSING PRACTICE APPLICATION
Patients Receiving Pharmacotherapy with Growth Hormone
Assessment
Baseline assessment prior to administration:
• Obtain a complete health history including cardiovascular, GI, hepatic, or kidney disease, diabetes, pregnancy, or breastfeeding. Obtain a growth and
development related history including congenital conditions such as Prader-Willi syndrome. Obtain a drug history including allergies, current prescrip-
tion and over-the-counter (OTC) drugs, herbal preparations, alcohol use, or smoking. Be alert to possible drug interactions.
• Evaluate appropriate laboratory findings (e.g., complete blood count [CBC], electrolytes, glucose, hepatic and renal function studies, thyroid hormone
panels, insulin-like growth factor-1 [IGF-1], IGF binding protein [IGFBP]).
• Obtain baseline height, weight, and vital signs. Obtain radiologic assessment of epiphyseal plates if ordered.
• Assess the patient’s ability to receive and understand instructions. Include family and caregivers as needed.
Assessment throughout administration:
• Assess for desired therapeutic effects dependent on the reason the drug is given (e.g., measurable increase in height, improved nutritional intake, weight).
• Continue periodic monitoring of CBC, electrolytes, glucose, hepatic and renal function studies, and thyroid and GH panels.
• Continue monitoring vital signs, height, and weight.
• Assess for adverse effects: nausea, vomiting, diarrhea, headache, peripheral edema, elevated serum glucose, joint pain, or muscle aches. Patients
with diabetes should promptly report consistent elevations in glucose.
Implementation
Interventions and (Rationales) Patient-Centered Care
Ensuring therapeutic effects: • Teach the patient, family, or caregiver to measure and record height
• Monitor height and weight at each clinical visit. Report lack of growth and weight weekly and bring the record to each clinical visit.
to the provider. (Lack of growth after a period of consistent growth may • Instruct the patient on the need to return periodically for laboratory work.
indicate the development of antibodies against GH or closure of the • Advise the patient, family, or caregiver of the cost of the drug before
epiphyseal plates.)
beginning therapy. Explore the ability to maintain drug therapy for the
duration of the treatment prescribed. Assess financial concerns and
provide appropriate social service referrals as needed.
Minimizing adverse effects: • Instruct the patient, family, or caregiver to report any changes in walk-
• Monitor for any reports of muscle, joint, or bone pain, particularly in ing, discomfort or pain in knee or hip joints, bone pain, or consistent
muscle pain over joint areas to the healthcare provider.
the knee or hip, or any changes in gait. (Carpal tunnel syndrome may
occur, especially with Serostim. Avascular necrosis is an adverse drug
effect of GH. Increasing or severe pain in joints or changes in gait
should be reported promptly for follow-up evaluation.)
• Monitor glucose levels, particularly in patients with diabetes. Report • Instruct the patient on the need to return periodically for laboratory work.
consistent elevations to the healthcare provider. (GH may cause • Teach patients with diabetes to monitor capillary glucose levels more
increases in glucose level. Patients with diabetes may need alterations
in their normal medication routines if hyperglycemia occurs.) frequently during therapy. Report any consistent elevations in blood
glucose to the healthcare provider.
• Continue to monitor vital signs, especially pulse and blood pres- • Instruct the patient to immediately report pounding headache, dizzi-
sure for patients with existing cardiac disease. Monitor daily weight, ness, palpitations, or syncope.
output, lung sounds, and for peripheral edema. (Fluid retention with an
increased intravascular volume, HTN, and peripheral edema may occur • Teach the patient, family, or caregiver how to monitor pulse and blood
in early therapy but should resolve over time. Immediately report any pressure as appropriate. Ensure the proper use and functioning of any
continuing or worsening symptoms to the healthcare provider.) home equipment obtained.
• Instruct the patient on how to monitor urine output if ordered, and pro-
vide measuring equipment as needed. Have the patient keep a record
of daily weight and output and bring the record to each clinical visit.
Chapter 65 Hypothalamic and Pituitary Drugs 1193
CONNECTIONS: NURSING PRACTICE APPLICATION (continued)
Implementation
Interventions and (Rationales) Patient-Centered Care
• Periodically monitor urine calcium levels, especially in the first few • Instruct the patient on the need to return periodically for laboratory
months of therapy. Report any flank pain, GI symptoms, or dysuria work.
to the healthcare provider. (Hypercalciuria may occur in early
therapy, sometimes without symptoms. Renal calculi are a
possible adverse effect.)
• Continue to monitor nutritional and fluid intake. (Wasting syndromes • Encourage increased fluid intake, up to 2 L/day if allowed, taken in
caused by conditions such as AIDS or CKD may result in nutritional frequent small amounts.
deficits and dehydration until the drug therapy is effective. Dietary
consultation may be required to reach and maintain optimal nutrition.) • Encourage small, high-calorie, nutrient-dense meals rather than large
infrequent meals.
• Obtain a dietary consult if the patient requests or if malnutrition is
severe.
Patient understanding of drug therapy: • The patient, family, or caregiver should be able to state the reason for
• Use opportunities during administration of medications and during the drug, appropriate dose and scheduling, what adverse effects to
observe for, and when to report them.
assessments to discuss the rationale for drug therapy, desired thera-
peutic outcomes, commonly observed adverse effects, parameters
for when to call the healthcare provider, and any necessary monitoring
or precautions. (Using time during nursing care helps to optimize and
reinforce key teaching areas.)
Patient self-administration of drug therapy: • Teach the patient to take the drug following appropriate guidelines:
• When administering the medication, instruct the patient, family, or • Reconstitute the parenteral drug exactly per package directions
and do not shake the vial; gently rotate it to avoid breaking down
caregiver in proper self-administration of the drug, e.g., during the the drug. Follow the manufacturer’s instruction if an automated pen
evening meal, followed by teach-back. (Utilizing time during nurse injector (e.g., Nutropin) is used.
administration of these drugs helps to reinforce teaching.) • Store any unused reconstituted solutions in the refrigerator; do not
freeze the solution. Discard any discolored solution or if particulate
matter is present.
• Administer GH drugs in the evening to mimic the body’s natural
rhythms.
• Administer subcutaneous injections in the abdomen, buttock, or
thigh areas, rotating injection sites. Do not use gluteal sites for
children under the age of 2; these muscles are not well developed
until the child has been walking for a year or more.
Pharmacotherapy of Antidiuretic levels and ADH secretion stops. Other factors stimulating
Hormone Disorders release of ADH include hypotension, decreased fluid vol-
ume, dehydration, pain, nausea, and vomiting. Factors
65.5 Pharmacotherapy is used to treat deficient inhibiting ADH release include decreased serum osmolal-
or excess secretion of antidiuretic hormone. ity and increased fluid volume. Many drugs also affect
ADH release, as listed in Table 65.5. ADH is also called
It is essential for the amount of fluid in the body to be vasopressin because it has the ability to cause vasoconstric-
maintained within narrow limits. Loss of large amounts of tion at high doses.
water leads to dehydration, a serious condition that can
lead to shock and death. Too much body fluid leads to con- Table 65.5 Drugs Interacting with Antidiuretic Hormone
gestion, edema, and water intoxication. Antidiuretic hor-
mone (ADH) is one of the most important means the body Drugs Stimulating Drugs Inhibiting
uses to maintain fluid balance homeostasis. For a complete ADH Secretion ADH Secretion
discussion of fluid balance and the drugs used as fluid
replacement agents, see Chapter 33. acetaminophen alcohol
anesthetics beta-adrenergic agonists
The hypothalamus senses fluid balance by recognizing barbiturates chlorpromazine
the osmolarity of the blood. Osmolarity is the number of carbamazepine demeclocycline
dissolved particles, or solutes, in a fluid. As water is lost, chlorpropamide heparin
the osmolality, or concentration of the blood, increases and corticosteroids lithium
the hypothalamus directs the posterior pituitary gland to diuretics norepinephrine
release ADH. This hormone acts on the renal tubules to tricyclic antidepressants opioids
enhance water reabsorption. The increased amount of phenytoin
water in the body reduces serum osmolality to normal
1194 Unit 10 Pharmacology of the Endocrine System
CONNECTION Checkpoint 65.2 ducts of the kidneys. In severe cases, IV infusion of a hyper-
tonic sodium chloride solution may be necessary to raise
In addition to ADH, the renin-angiotensin-aldosterone system (RAAS) serum osmolality.
is essential for maintaining fluid balance. From what you learned
in Chapter 31, how does the RAAS affect sodium and water bal- PharmFACT
ance? Answers to Connection Checkpoint questions are available on
the faculty resources site. Please consult with your instructor. Diabetes insipidus is uncommon with a prevalence of 3 cases
per 100,000 people. Thirty percent of the cases are idiopathic
A deficiency in ADH results in diabetes insipidus (DI), a with no identifiable cause (Khardori, 2017).
condition characterized by the production of large vol-
umes of very dilute urine, usually accompanied by PROTOTYPE DRUG Desmopressin (DDAVP,
increased thirst. DI may be either nephrogenic or neuro- Noctiva, Stimate)
genic. Nephrogenic DI is caused by the inability of the
kidneys to respond to ADH. Drugs, such as lithium Classification Therapeutic: Antidiuretic hormone
(Eskalith), or electrolyte disturbances can cause nephro- replacement, drug for nocturia
genic DI. Because nephrogenic DI results from an inabil-
ity to respond to ADH, replacement therapy is not Pharmacologic: Pituitary hormone
effective.
Therapeutic Effects and Uses: Approved in 1978,
Neurogenic or central DI results from a lack of ade- desmopressin is a synthetic analog of human ADH that
quate production or secretion of ADH in the brain. The has a longer duration of action than the natural hormone.
etiology of neurogenic DI can be genetic or acquired fol- It controls the acute symptoms of polyuria and polydip-
lowing head injury, surgery, tumors, infections, or vascu- sia in patients with neurogenic DI but not nephrogenic
lar lesions of the region. The preferred drug for treating diabetes insipidus. For DI, the PO route is preferred,
chronic neurogenic DI is desmopressin (DDAVP). Chlor- although IV and subcutaneous forms are available for
propamide, a hypoglycemic drug, can be used to stimulate SIADH.
ADH release in partial neurogenic DI. Paradoxically, both
forms of DI respond in part to thiazide diuretics such as Desmopressin has vasoconstrictor activity that
hydrochlorothiazide. causes contraction of smooth muscle in the vascular sys-
tem, uterus, and GI tract. It produces fewer vasoconstric-
The primary symptoms of DI are polyuria and poly- tive effects than natural vasopressin. Desmopressin also
dipsia (excessive thirst). Extremely large volumes of fluid produces an increase in plasma Factor VIII and von Wil-
(up to 30 L/day) may be ingested and the urine will be lebrand’s factor and is thus indicated for the manage-
very dilute. The intense thirst and frequent urination usu- ment of bleeding in patients with hemophilia A and von
ally keep patients awake during the night. Failure to ensure Willebrand’s disease (type I). Desmopressin is available
adequate fluid intake will result in hypovolemia and dehy- in IV and intranasal (Stimate) forms for these indica-
dration due to the large renal water loss. tions. The use of desmopressin in treating coagulation
disorders is presented in Chapter 38. This drug is the
Excess secretion of ADH is the cause of the syndrome most effective pharmacologic intervention for control-
of inappropriate antidiuretic hormone (SIADH), a condi- ling enuresis (bedwetting) in children. For enuresis, des-
tion characterized by marked fluid retention, elevated mopressin is administered 1 hour before bedtime in
urine osmolality, low serum osmolality, and sodium loss in children age 6 or older, for up to 6 months. In 2017, an
the urine. SIADH may occur as a transient or chronic con- intranasal form (Noctiva) was approved to treat noctur-
dition. The resulting hyponatremia and water retention nal polyuria in adults who awaken at least 2 times per
cause muscle cramps, weakness, headache, apprehension, night to void.
nausea, vomiting, and lethargy, progressing to stupor and
coma. Treatment involves fluid restriction and diuretics Mechanism of Action: Desmopressin increases the
such as mannitol or furosemide (Lasix) to remove excess permeability of renal collecting tubules to water, thereby
fluid. Conivaptan (Viprostol) and tolvaptan (Samsca) are increasing the reabsorption of water. It produces vasocon-
vasopressin receptor antagonists that promote renal water striction of blood vessels at higher doses. The vasocon-
excretion and increased serum sodium levels in patients striction produced is greatest in portal vessels and less
with SIADH. The antibiotic demeclocycline (Declomycin) in cerebral, coronary, pulmonary, and peripheral vessels.
is a tetracycline used off-label to treat SIADH due to its Desmopressin enhances GI motility and tone through con-
ability to cause diuresis through the inhibition of ADH- traction of smooth muscle in the GI tract.
induced water reabsorption in the tubules and collecting
Chapter 65 Hypothalamic and Pituitary Drugs 1195
Pharmacokinetics: Nursing Practice Application for Patients Receiving Phar-
macotherapy with Antidiuretic Hormone.
Route(s) Subcutaneous, IV, PO
Drugs Similar to Desmopressin (DDAVP,
Absorption 5% through GI mucosa Noctiva, Stimate)
Distribution Small amount may cross the The only drug that is similar to desmopressin is vasopressin.
blood–brain barrier; secreted in Vasopressin: A synthetic analog of antidiuretic hormone,
vasopressin is given IM or subcutaneously for central or
breast milk neurogenic DI. Approved in 1941, it has a shorter duration
of action than desmopressin and a more pronounced vaso-
Primary metabolism Metabolized rapidly by the liver constrictor action, which can result in serious adverse
effects.
Primary excretion Renal
Because vasopressin is a potent vasoconstrictor, it is
Onset of action PO: 1 h, with a peak at 4–7 h; given IV as an alternative to epinephrine for many off-label
indications. These include bleeding from esophageal vari-
IV: 1 min with a peak at 30 min; ces or the upper GI tract, cardiac arrest, and the treatment
of severe hypotension or shock. Vasopressin may precipi-
intranasal: 30 min with a peak tate MI or angina. It may cause water intoxication. When
used for its vasopressor effects, possible adverse effects
of 1.5 h include tissue necrosis and gangrene. Vasopressin is a
pregnancy category C drug.
Duration of action PO: 8–20 h; IV: 3 h
CONNECTION Checkpoint 65.3
Adverse Effects: Desmopressin can cause water
intoxication. Early signs include drowsiness, headache, Desmopressin is used to treat von Willebrand’s disease, the most
and listlessness, progressing to convulsions and coma. common inherited coagulation disorder. From what you learned in
Other adverse effects include transient headache, nau- Chapter 38, what is the function of von Willebrand’s factor? Answers
sea, mild abdominal pain and cramping, facial flush- to Connection Checkpoint questions are available on the faculty
ing, HTN, or pain or swelling at the injection site. A rare resources site. Please consult with your instructor.
adverse effect of desmopressin is a severe allergic reac-
tion or anaphylaxis (IV administration). Tolerance to the CONNECTIONS: Treating the
effects of desmopressin develops when it is administered Diverse Patient
more frequently than every 48 hours or by the IV route.
The intranasal route may cause local irritation, rhini- Gender Differences in Desmopressin Dose
tis, and congestion. Black Box Warning: Noctiva may for Nocturia in Adults
cause hyponatremia, which can be severe and even life
threatening. Although nocturnal enuresis is commonly considered a
childhood condition, it occurs in the adult population as
Contraindications/Precautions: Desmopressin is well. Excessive fluid intake and alcohol use are known
contraindicated in patients with nephrogenic DI. It is used causative factors. Increasing age and female gender are
with caution in patients with coronary artery disease, risk factors for desmopressin-induced hyponatremia, sec-
HTN, and in patients with a history of hyponatremia or ondary to fluid retention. It has been shown that women
thrombi. The drug is contraindicated in patients with CKD have a higher sensitivity to vasopressin in the kidneys,
because the drug can worsen fluid retention and overload. which leads to a fivefold higher risk of hyponatremia for
Young children and the older adult should be treated with women over age 50 than men. Berges, Höfner, Gedamke,
caution because these patients are more prone to water and Oelke (2014) concluded that equivalent doses of des-
intoxication and hyponatremia. mopressin resulted in lower overall efficacy in men com-
pared to women and that the standard dose of 0.1 and
Drug Interactions: Increased antidiuretic action can 0.4 mg daily does not increase the risk of developing hypo-
occur with carbamazepine, chlorpropamide, and non- natremia in men. Additional large-scale clinical trials need
steroidal anti-inflammatory drugs (NSAIDs). Decreased to be conducted to verify and determine appropriate doses
antidiuretic action can occur with lithium, alcohol, hepa- for men and women.
rin, and epinephrine. Herbal/Food: Unknown.
Pregnancy: Category B.
Treatment of Overdose: In case of overdose, or if
water intoxication develops, symptomatic treatment with
diuretics is recommended.
Nursing Responsibilities: Key nursing implications
for patients receiving desmopressin are included in the
1196 Unit 10 Pharmacology of the Endocrine System
CONNECTIONS: NURSING PRACTICE APPLICATION
Patients Receiving Pharmacotherapy with Antidiuretic Hormone
Assessment
Baseline assessment prior to administration:
• Obtain a complete health history including cardiovascular, GI, hepatic or kidney disease, pregnancy, or breastfeeding. Obtain a drug history including
allergies, current prescription and OTC drugs, herbal preparations, alcohol use, or smoking. Be alert to possible drug interactions.
• Evaluate appropriate laboratory findings (e.g., urine and serum osmolality, urine specific gravity, serum protein, CBC, electrolytes, hepatic and renal
function studies).
• Obtain baseline height, weight, and vital signs.
• Assess the patient’s ability to receive and understand instructions. Include family and caregivers as needed.
Assessment throughout administration:
• Assess for desired therapeutic effects dependent on the reason the drug is being given (e.g., diuresis slows and urine output and serum osmolality
return to normal, bleeding stops or slows).
• Continue periodic monitoring of urine and serum osmolality, urine specific gravity, CBC, electrolytes, serum protein, hepatic and renal function studies.
• Continue monitoring vital signs and weight.
• Assess for adverse effects: nausea, vomiting, diarrhea, headache, nasal congestion, or rhinitis. Immediately report drowsiness, dizziness, lethargy,
hypotension or HTN, tachycardia, dysrhythmias, or angina to the healthcare provider.
Implementation
Interventions and (Rationales) Patient-Centered Care
Ensuring therapeutic effects: • Teach the patient, family, or caregiver to measure and record height
• For patients with DI, monitor urine output, urine and serum osmolality, and weight weekly and bring the record to each clinical visit.
and urine specific gravity for return to normal limits. If given for noctur- • Instruct the patient on the need to return periodically for laboratory work.
nal enuresis, have the patient or family keep a diary of sleep patterns, • Instruct the patient to monitor output (provide measuring equipment as
noting any bedwetting. (Urine output, osmolality, and specific gravity
should return to normal limits. Bedwetting should decrease or stop.) needed) and to keep a record of daily weight and output.
• Teach the patient, family, or caregiver to keep a diary of nighttime sleep
habits and any bedwetting. Limit oral fluids within 4 h of bedtime. Bring
the record to each clinical visit.
• Advise the patient of the cost of the drug before beginning therapy.
Explore the ability to maintain drug therapy for the duration of the treat-
ment prescribed. Assess financial concerns and provide appropriate
social service referral as needed.
Minimizing adverse effects: • Instruct the patient to immediately report pounding headache, dizzi-
• Continue to monitor vital signs, especially pulse and blood pressure for ness, palpitations, or syncope.
patients with existing cardiac disease. ECGs may be ordered periodi- • Teach the patient, family, or caregiver how to monitor pulse and blood
cally for patients with a history of dysrhythmias. Monitor daily weight, pressure as appropriate. Ensure proper use and functioning of any
urine output, level of consciousness (LOC), lung sounds, and for home equipment obtained.
peripheral edema. (Fluid retention secondary to antidiuretic hormone
treatment may lead to increased intravascular volume, HTN, and water • Instruct the patient to monitor urine output (provide measuring equip-
intoxication.) ment as needed) and to keep a record of daily weight and urine output.
• Instruct the patient, family, or caregiver to immediately report any drowsi-
ness, dizziness, lethargy, or decreased LOC to the healthcare provider.
• Continue to monitor laboratory studies, especially serum sodium levels • Instruct the patient on the need to return periodically for laboratory
and osmolality. (DI or water retention triggered by the use of ADH work.
replacement may result in alterations in serum sodium and osmolality.
Lifespan: Normal physiologic changes may place the older adult at
greater risk for adverse effects related to electrolyte or fluid changes.)
• Monitor for and immediately report signs of peripheral ischemia, HTN, • Instruct the patient to immediately report any chest pain, pain or numb-
or angina. (Vasoconstriction caused by vasopressin may cause cardiac ness in toes or fingers, or cramping when walking to the healthcare
or peripheral ischemia, angina, or infarction.) provider.
• Monitor nasal passages. Report any excoriation or bleeding. (Long- • Teach the patient to report nasal congestion, irritation, increase in nasal
term intranasal ADH therapy may cause nasal irritation and ulceration.) discharge, or bleeding to the healthcare provider.
Patient understanding of drug therapy: • The patient, family, or caregiver should be able to state the reason for
• Use opportunities during administration of medications and during the drug, the appropriate dose and scheduling, what adverse effects to
observe for, and when to report them.
assessments to discuss the rationale for drug therapy, desired thera-
peutic outcomes, commonly observed adverse effects, parameters
for when to call the healthcare provider, and any necessary monitoring
or precautions. (Using time during nursing care helps to optimize and
reinforce key teaching areas.)
Patient self-administration of drug therapy: • Teach the patient to take the drug following appropriate guidelines:
• When administering the medication, instruct the patient or caregiver in • Direct nasal sprays high into the nasal cavity rather than back to
the nasopharynx. Do not shake a nasal spray before using; gently
proper self-administration of the drug, e.g., during the evening meal, rotate it.
followed by teach-back. (Utilizing time during nurse administration of • Store any unused solutions in the refrigerator. Nasal sprays may be
these drugs helps to reinforce teaching.) kept at room temperature but avoid excessive heat over 26.7°C
(80°F). Discard any discolored solution or if particulate matter is
present.
Chapter 65 Hypothalamic and Pituitary Drugs 1197
Understanding Chapter 65
Key Concepts Summary 65.4 Overproduction of growth hormone in adults
can be treated by administering growth hormone
65.1 The hypothalamus controls many diverse body antagonists.
processes and secretes hormones that influence
pituitary function. 65.5 Pharmacotherapy is used to treat deficient or excess
secretion of antidiuretic hormone.
65.2 The pituitary gland secretes hormones that control
many diverse body functions.
65.3 Growth hormone deficiency in adults and children
can be treated by administering recombinant
growth hormone.
CASE STUDY: Making the Patient Connection
Remember the patient find out that, although there is a problem, it is not due to a
“Raj” at the beginning of tumor or other life-threatening disorder. Raj has a congeni-
the chapter? Now read the tal deficiency in GH, and the pediatrician discusses replace-
remainder of the case ment therapy with the parents. They agree that Raj should
study. Based on the infor- have this therapy and want to start it as soon as possible.
mation presented in this Somatropin (Humatrope) has been ordered. As the nurse
chapter, answer the criti- working with Raj and his family, address each of the fol-
cal thinking questions that follow. lowing questions.
Raj, an 8-year-old boy, was referred to the pediatric endo- Critical Thinking Questions
crinology clinic for evaluation of his short stature. He had
been healthy and developmentally normal until 3 years 1. What teaching will you need to provide to Raj’s par-
ago. Since that time, his growth has been extremely slow— ents regarding drug therapy for his disorder?
in fact, almost imperceptible. On his initial examination,
Raj’s weight and height were 17 kg (37.4 lb) and 108 cm 2. Raj’s father states, “I hope my health insurance will
(42.5 in.), respectively. His height standard deviation score cover this medication.” What would you say in
was –4.0 with a body mass index of 14.6. The remainder of response to this comment?
his physical examination was normal.
3. The parents ask about the adverse effects that might
When the pediatrician reviewed the results of hor- occur with this therapy. How would you respond?
monal tests with Raj’s parents, everyone was relieved to
Answers to Critical Thinking Questions are available on the
faculty resources site. Please consult with your instructor.
Additional Case Study 1. What type of pharmacotherapy do you anticipate for
Edward?
Edward Keithy, a 10-year-old boy, and his parents visit the
pediatrician’s office where you are a nurse. The parents are 2. What information will Edward and his parents need as
concerned with Edward’s continuing nocturnal enuresis, part of patient drug teaching?
or nighttime bedwetting. Increasingly, they see this condi-
tion as adversely affecting his self-image, self-esteem, and Answers to Additional Case Study questions are available on
psychosocial well-being. Edward tells you that he is reluc- the faculty resources site. Please consult with your instructor.
tant to take part in sleepovers at his friends’ houses or to
attend camping trips with his scouting troop.
1198 Unit 10 Pharmacology of the Endocrine System
Chapter Review 4. A patient with metastatic colon cancer is experiencing
bowel-related complications of the cancer and treat-
1. A teaching plan for a parent whose child is receiving ment. Octreotide (Sandostatin) has been ordered. The
somatropin (Nutropin) should include what impor- nurse will anticipate which therapeutic effect from
tant information? this drug?
1. The patient must adhere to therapy to prevent 1. Decrease in the number of diarrheal stools per day
mental retardation. 2. Slowing of the metastatic spread of the cancer
3. Increase in lean body mass and fat deposits
2. The medication cannot be given orally; it can be 4. Episodes of hypo- or hyperglycemia
given only parenterally.
5. Prior to starting a patient on octreotide (Sandostatin)
3. If growth hormone is begun in adolescence, it can for control of esophageal varices, the nurse will obtain
add up to 15 cm (6 in.) in height. the patient’s past health history. If present, what con-
dition might indicate the need to verify the order with
4. Growth hormone therapy requires frequent blood the prescriber?
work.
1. Glaucoma
2. Which of the following findings would the nurse con- 2. Alcoholism
sider to be effects of somatropin? (Select all that 3. Chronic obstructive pulmonary disease (COPD)
apply.) 4. Diabetes
1. Increase in the length and width of long bones 6. Which of the following assessment findings would
2. Organ, muscle, and connective tissue growth indicate that therapeutic goals have been achieved for
3. Increased synthesis of proteins a patient with diabetes insipidus being treated with
4. Lowering of serum glucose levels desmopressin (DDAVP)?
5. Increase in fat deposits around the abdomen
1. Decreasing signs of dehydration
3. The patient with neurogenic diabetes insipidus is 2. Increasing pulse and urine output
being started on an oral dose of desmopressin 3. Decreasing urine specific gravity
(DDAVP). Which instruction should the nurse include 4. Decreasing hyperglycemia
in the teaching plan?
See Answers to Chapter Review in Appendix A.
1. Use the drug only if urine output is excessive.
2. Use twice the prescribed dose if you miss a dose.
3. Obtain and record your weight each morning.
4. Use an NSAID such as ibuprofen if leg cramping
occurs during walking.
References Lauzier, F., Turgeon, A. F., Boutin, A., Shemilt, M., Côté, I.,
Lachance, O., . . . Cook, D. (2014). Clinical outcomes,
Berges, R., Höfner, K., Gedamke, M., & Oelke, M. (2014). predictors, and prevalence of anterior pituitary
Impact of desmopressin on nocturia due to nocturnal disorders following traumatic brain injury: A
polyuria in men with lower urinary tract symptoms systematic review. Critical Care Medicine, 42, 712–721.
suggestive of benign prostatic hyperplasia (LUTS/ doi:10.1097/CCM.0000000000000046
BPH). World Journal of Urology, 32, 1163–1170.
doi:10.1007/s00345-014-1381-7 Rose, S. C., Weber, K. D., Collen, J. B., & Heyer, G. L.
(2015). The diagnosis and management of concussion
Khardori, R. (2017). Diabetes insipidus. Retrieved from in children and adolescents. Pediatric Neurology, 53,
http://emedicine.medscape.com/article/ 108–118. doi:10.1016/j.pediatrneurol.2015.04.003
117648-overview
Chapter 65 Hypothalamic and Pituitary Drugs 1199
Selected Bibliography National Institutes of Health, National Institute of
Neurological Disorders and Stroke. (n.d.). Traumatic
Broder, M. S., Chang, E., Ludlam, W. H., Neary, M. P., & brain injury information page. Retrieved from https://
Carmichael, J. D. (2016). Patterns of pharmacologic www.ninds.nih.gov/Disorders/All-Disorders/
treatment in US patients with acromegaly. Current Traumatic-Brain-Injury-Information-Page
Medical Research and Opinion, 32, 799–805. doi:10.1185/0
3007995.2015.1125870 Peri, A., Grohé, C., Berardi, R., & Runkle, I. (2017). SIADH:
Differential diagnosis and clinical management.
Bujanova, J., & Cummings, M. H. (2015). Management of Endocrine, 55, 311–319. doi:10.1007/s12020-016-0936-3
growth hormone deficiency in adults. Prescriber, 26,
29–33. doi:10.1002/psb.1422 Plunkett, C., & Barkan, A. L. (2015). The care continuum in
acromegaly: How patients, nurses, and physicians can
Collin, J., Whitehead, A., & Walker, J. (2016). Educating collaborate for successful treatment experiences. Patient
children and families about growth hormone deficiency Preference and Adherence, 9, 1093–1099. doi:10.2147/PPA.
and its management: Part 2. Nursing Children and Young S84887
People, 28(2), 30–36. doi:10.7748/ncyp.28.2.30.s23
Robson, L. M. (2016). Enuresis. Retrieved from http://
Diaz-Thomas, A. (2017). Gigantism and acromegaly. emedicine.medscape.com/article/1014762-overview
Retrieved from http://emedicine.medscape.com/
article/925446-overview#a1 Roth, K. S. (2017). Pediatric diabetes insipidus. Retrieved
from http://emedicine.medscape.com/article/
Höybye, C., & Christiansen, J. S. (2015). Growth hormone 919886-overview
replacement in adults—current standards and new
perspectives. Best Practice & Research Clinical Teran, E., Chesner, J., & Rapaport, R. (2016). Growth and
Endocrinology & Metabolism, 29, 115–123. doi:10.1016/j. growth hormone: An overview. Growth Hormone & IGF
beem.2014.09.006 Research, 28, 3–5. doi:10.1016/j.ghir.2016.02.004
Malanowski, S., & Baima, N. (2015). On treating athletes Thomas, C. P. (2017). Syndrome of inappropriate antidiuretic
with banned substances: The relationship between mild hormone secretion. Retrieved from http://emedicine.
traumatic brain injury, hypopituitarism, and hormone medscape.com/article/246650-overview
replacement therapy. Neuroethics, 8, 27–38. doi:10.1007/
s12152-014-9215-2
“Diabetes?! How can I have
diabetes? I don’t eat a lot of
sugar; I try to watch my weight.
And what is this type 2 thing
about?”
Patient “Eileen Douglas”
Chapter 66
Pharmacotherapy
of Diabetes Mellitus
Chapter Outline Learning Outcomes
cc Physiology of Serum Glucose Control After reading this chapter, the student should be able to:
cc Pathophysiology of Diabetes Mellitus: Types of
1. Explain how blood glucose levels are maintained
Diabetes within narrow limits by insulin and glucagon.
cc Symptoms and Diagnosis of Diabetes
cc Complications of Diabetes Mellitus 2. Compare and contrast the etiology and pathogenesis
of type 1, type 2, and gestational diabetes.
PROTOTYPE Glucagon (GlucaGen), p. 1205
cc Insulin Therapy 3. Describe the signs and diagnosis of diabetes.
PROTOTYPE Human Regular Insulin 4. Describe the acute complications of diabetes.
(Humulin R, Novolin R), p. 1209
cc Antidiabetic Drugs for Type 2 Diabetes 5. Identify the chronic complications of diabetes.
Sulfonylureas
PROTOTYPE Glyburide (DiaBeta, Glynase), p. 1215 6. Compare and contrast the pharmacotherapy of the
Biguanides different types of diabetes.
PROTOTYPE Metformin (Glucophage,
Glumetza, Others), p. 1217 7. For each type of insulin, identify the onset of action,
Meglitinides peak action and duration of action, administration
PROTOTYPE Repaglinide (Prandin), p. 1218 routes, when it is given related to meals,
Thiazolidinediones compatibility with other insulins, and adverse
PROTOTYPE Rosiglitazone (Avandia), p. 1219 effects.
Alpha-Glucosidase Inhibitors
PROTOTYPE Acarbose (Precose), p. 1220 8. For each of the classes shown in the chapter outline,
Incretin Therapies identify the prototype and representative drugs and
PROTOTYPE Sitagliptin (Januvia), p. 1221 explain the mechanism(s) of drug action, primary
cc Miscellaneous Antidiabetic Drugs indications, contraindications, significant drug
interactions, pregnancy category, and important
adverse effects.
9. Apply the nursing process to the care of patients
receiving pharmacotherapy for diabetes.
1200
Chapter 66 Pharmacotherapy of Diabetes Mellitus 1201
Key Terms hyperosmolar hyperglycemic state polydipsia, 1203
(HHS), 1204 polyphagia, 1203
diabetes mellitus, 1202 polyuria, 1203
diabetic ketoacidosis (DKA), 1204 incretins, 1221 prediabetes, 1204
fasting plasma glucose type 1 diabetes, 1202
insulin, 1201 type 2 diabetes, 1202
(FPG) test, 1203
gestational diabetes, 1203 insulin resistance, 1202
gluconeogenesis, 1201
glycogenolysis, 1201 metabolic syndrome, 1204
hemoglobin A1C test, 1203
oral glucose tolerance test
(OGTT), 1203
It is estimated that over 29 million people in the United stable serum glucose level: insulin, which acts to decrease
States have diabetes mellitus, with more than 8 million of blood glucose levels, and glucagon, which acts to increase
those being undiagnosed. Diabetes is one of the leading blood glucose levels.
causes of death in the United States. Mortality has risen in
recent years, causing some public health officials to refer to Following a meal, glucose is rapidly absorbed from the
it as an epidemic. Diabetes can lead to serious acute and gastrointestinal (GI) tract, and serum levels rise. Some of
chronic complications, including heart disease, stroke, the glucose is taken up by cells and used for immediate
blindness, kidney failure, and amputations. Because nurses energy needs, but about two thirds is stored in liver and
frequently care for patients with diabetes, it is imperative muscle cells as glycogen, the storage form of glucose. When
that they thoroughly understand the disorder, its treat- glucose levels fall between meals, glycogen is broken down
ment, and possible complications. There is an unrelated in a process called glycogenolysis, and glucose is released
disorder, diabetes insipidus, which results from a defi- into the bloodstream. Maintaining a stable serum glucose
ciency of antidiuretic hormone (see Chapter 65). When the level is simply a matter of storing glucose during times of
term diabetes is used in this chapter, it is referring to diabe- excess, and returning it to the bloodstream in times of defi-
tes mellitus. ciency. The importance of maintaining this delicate bal-
ance, however, cannot be overstated. Too much glucose or
Physiology of Serum Glucose too little glucose can have lethal consequences.
Control
Following a meal, the pancreas recognizes the rising
66.1 Serum glucose is maintained within serum glucose levels and releases insulin. Without insu-
a narrow range by the hormones insulin lin, glucose is not able to enter cells of the body. The cells
and glucagon. may be surrounded by high amounts of glucose but they
are unable to use it until insulin arrives. It may be helpful
Because diabetes is essentially a disorder of carbohydrate to visualize insulin as a transporter or “gatekeeper.”
metabolism, it is important to understand the way the When present, insulin swings open the gate, transporting
body obtains, metabolizes, and stores glucose. Of all the glucose inside cells—if there is no insulin, there is no
different molecules available, the body prefers to use glu- entry. The physiologic actions of insulin are summarized
cose as its primary energy source. The brain relies almost as follows:
exclusively on glucose for its energy needs because it is
unable to synthesize glucose and it will exhaust its supply • It promotes the entry of glucose into cells.
after just a few minutes of activity. Most other tissues can • It provides for the storage of glucose, as glycogen.
use fatty acids and proteins for energy production, if nec- • It inhibits the breakdown of fat and glycogen.
essary, but they too prefer to use glucose. One of the most • It increases protein synthesis and inhibits gluconeo-
important roles of the liver and pancreas is to regulate the
body’s carbohydrate fuel supply so that all tissues of the genesis, which is the production of new glucose from
body have sufficient energy to perform their functions. noncarbohydrate molecules.
Although the normal range for serum glucose is con- Insulin is produced in beta cells of the pancreas known
sidered to be 60 to 100 mg/dL, it is usually tightly regu- as islets of Langerhans, whereas alpha cells in the pancreas
lated by the body to remain between 80 and 90 mg/dL. secrete glucagon. Glucagon maintains stable blood glucose
Two pancreatic hormones contribute to maintaining a levels between meals and during periods of fasting and has
actions that are opposite to those of insulin. It removes glu-
cose from its storage in the liver and sends it to the blood
(glycogenolysis), raising serum glucose within minutes.
1202 Unit 10 Pharmacology of the Endocrine System
The level of glucose in the blood regulates the release High blood glucose Low blood glucose
of both insulin and glucagon. A hypoglycemic state (low
serum glucose) stimulates the release of glucagon and Pancreas releases Pancreas releases
inhibits the release of insulin, whereas a hyperglycemic insulin glucagon
state (high serum glucose) has the opposite effect: It stimu-
lates the release of insulin and inhibits the release of gluca- Cells take Liver produces Liver breaks
gon. The physiologic dynamics of insulin and glucagon up glucose glycogen down glycogen
release are shown in Figure 66.1. from blood
Additional factors that decrease blood glucose levels Blood glucose falls Blood glucose rises
are fasting, exercise, and alcohol. Factors that increase
blood glucose levels include stress from infection, injury, or (a) (b)
surgery, which triggers release of the epinephrine and nor-
epinephrine; large meals or overconsumption of carbohy- Figure 66.1 Insulin, glucagon, and blood glucose.
drates; growth hormone; and corticosteroids.
dangerous and potentially life-threatening condition (see
PharmFACT Section 66.4).
According to the American Diabetes Association (ADA, Patients with type 1 diabetes must receive insulin ther-
2017), the incidence of diabetes mellitus in the United States apy to survive. In the past, type 1 was called juvenile or
is as follows: insulin-dependent diabetes. Although these terms are still
in use, they do not accurately reflect the nature of the
• 1 in every 400 children and adolescents has diabetes. disease.
• 9.4% of all people 20 years or older have diabetes.
• 25% of all people 65 years or older have diabetes. Type 2 diabetes is the more common form of the disor-
• 1.5 million new cases of adult diabetes are diagnosed der, representing 90% to 95% of people with diabetes. The
primary physiologic characteristic of type 2 diabetes is
each year. hyperglycemia, caused by a relative deficiency of insulin.
The disorder is characterized by insulin resistance, a con-
Pathophysiology of Diabetes dition in which cells become unresponsive to insulin due to
Mellitus: Types of Diabetes a defect in insulin receptor function. The pancreas may be
secreting sufficient amounts of insulin but target cells do
66.2 Type 1 diabetes is characterized by not recognize it.
insufficient insulin synthesis by the pancreas,
whereas type 2 diabetes is characterized by As cells become increasingly resistant, blood glucose
insulin resistance in the target cells. levels rise and the pancreas responds by secreting even
more insulin. Eventually, the hypersecretion of insulin
Diabetes mellitus is a metabolic disorder characterized by leads to beta cell exhaustion and, ultimately, to beta cell
an imbalance between insulin availability and insulin death. As type 2 diabetes progresses, it becomes a disorder
need. The two primary forms of diabetes are called type 1 characterized by insufficient insulin levels as well as insu-
and type 2. There are significant differences between the lin resistance. The activity of insulin receptors can be
two types in terms of pathophysiology and disease man- increased by exercise, which lowers the level of circulating
agement. A third form of the disease occurs during preg- insulin. In fact, adhering to a healthy diet and regular exer-
nancy and is known as gestational diabetes. cise have been shown to reverse insulin resistance and to
delay or prevent the development of type 2 diabetes.
Type 1 diabetes results from an absolute lack of insulin
secretion due to destruction of pancreatic beta cells. The Eighty percent of people with type 2 diabetes are over-
destruction of beta cells is believed to result from a combi- weight, and the degree of obesity directly affects the
nation of autoimmune, genetic, and environmental factors. degree of insulin resistance. In particular, individuals with
Type 1 is the less common form of diabetes, accounting for
only 5% to 10% of all patients with the disorder. It is seen
most frequently among children and young adults, but it
may occur at any age.
Because of the lack of sufficient insulin in patients with
type 1 diabetes, glucose cannot enter cells and fatty acids
are used as the primary energy source. Metabolic by-prod-
ucts of lipid metabolism known as ketones accumulate in
the blood, producing diabetic ketoacidosis (DKA), a
Chapter 66 Pharmacotherapy of Diabetes Mellitus 1203
Table 66.1 Comparison of Type 1 and Type 2 Diabetes five or more pregnancies, or women who are members of a
high-risk population (Hispanic, Native American, Asian,
Mellitus or African American). If careful nutritional management
combined with an approved exercise plan is unable to nor-
Diabetes Mellitus Type 1 Type 2 malize serum glucose levels, insulin therapy is initiated.
Cause Traditionally, oral antidiabetic drugs have not been used
Destruction of beta Insulin resistance in for gestational diabetes due to concerns regarding potential
Incidence cells causing lack of target cells; insulin teratogenicity; however, the results of research may change
Age at onset insulin deficiency may develop that practice in the future.
90–95%
Symptom onset 5–10% Usually older than Symptoms and Diagnosis
Body weight 35 years but incidence of Diabetes
Children, young increasing in children
adults, usually 66.3 The classic signs and symptoms of diabetes
younger than Gradual include polyuria, polydipsia, and polyphagia.
35 years Usually overweight or
obese The classic triad of signs and symptoms for either type of
Rapid Same as type 1, plus diabetes is known as the three “polys”: polyuria, excessive
blurred vision, fatigue, urine production; polydipsia, excessive thirst; and poly-
Usually underweight recurrent infections phagia, excessive appetite.
Infrequent
Symptoms Polyuria, polydipsia, Glucose is one of the body’s most valuable energy mol-
polyphagia, weight Oral antidiabetes drugs ecules, and nondiabetic patients excrete very little. As glu-
Ketosis loss with or without insulin cose levels rise in the blood in patients with diabetes,
Pharmacologic however, the kidneys are unable to reabsorb the large
treatment Often present with amounts passing through the renal tubules, so glucose is
poor control eliminated in the urine (glucosuria). Glucose molecules cre-
ate increased osmotic pressure in body fluids, pulling water
Insulin replacement along with it; thus, osmotic diuresis (polyuria) occurs. The
glucose increases osmotic pressure in the bloodstream, pull-
upper body obesity (central or visceral obesity) are at ing water out of tissue cells and causing cellular dehydra-
increased risk for developing insulin resistance and type 2 tion. This triggers thirst and causes the individual to
diabetes. Although most patients with type 2 diabetes are increase fluid intake (polydipsia). The excess hunger (poly-
older, this disease is increasingly being diagnosed in ado- phagia) occurs primarily with type 1 diabetes, when nutri-
lescents with obesity. Risk factors for type 2 diabetes are a ent stores become too depleted to meet the body’s energy
family history of diabetes, obesity, and race and ethnicity. needs and weight is lost. Other signs and symptoms include
Hispanics/Latinos, non-Hispanic African Americans, and blurred vision, fatigue, paresthesias, and skin infections.
Asian Americans are at increased risk for type 2 diabetes Nocturia, secondary to the polyuria, may occur.
(ADA, 2015). Other risk factors are age older than 45 years;
a history of elevated fasting serum glucose levels or Although symptomology is important for recognizing
impaired glucose tolerance; hypertension (HTN); low the possibility of diabetes, many patients with the disease
levels of high-density lipoproteins; triglycerides above have no symptoms. Laboratory tests are required for proper
250 mg/dL; and a history of gestational diabetes or deliv- diagnosis. The primary blood tests for diagnosing diabetes
ery of a baby over 9 pounds, or both. Table 66.1 compares are the fasting plasma glucose (FPG) test, oral glucose tol-
and contrasts type 1 and type 2 diabetes. erance test (OGTT), and hemoglobin A1C test.
Most patients with type 2 diabetes do not require insu- • FPG: obtained following a fast of at least 8 hours. A
lin administration, at least initially; their condition can be value of 126 mg/dL or higher indicates diabetes.
managed with oral antidiabetic drugs. Type 2 diabetes was
formerly called adult-onset diabetes and non–insulin- • OGTT: A loading dose of 75 g of glucose is ingested
dependent diabetes, but these are not accurate descriptions and the plasma glucose level is obtained 2 hours later.
of the disorder because it occurs in children and may A value of 200 mg/dL or higher indicates diabetes.
require insulin administration.
• A1C: As serum glucose increases, more glucose
Gestational diabetes is a condition resulting from glu- becomes bound to hemoglobin. A value of 6.5% or
cose intolerance with an onset, or first recognition, during higher indicates diabetes. The advantage of the A1C
pregnancy. This is a serious disorder that puts both the test is that it does not require fasting and it provides
woman and fetus at risk for complications and so requires an average measure of glucose control over the 8 to
careful management during pregnancy. In addition, 12 weeks prior to the test.
women who develop gestational diabetes are at increased
risk for developing diabetes 5 to 10 years after delivery. It
occurs most frequently in women with a family history of
diabetes, a history of stillbirth or spontaneous abortion, a
previous large-for-gestational-age baby, women who are
obese or of advanced maternal age, women who have had
1204 Unit 10 Pharmacology of the Endocrine System
Home monitoring of blood glucose is now common- three primary acute conditions. The chronic complications
place and enables the patient with diabetes to maintain are discussed in Section 66.5.
tighter control of glucose levels. Fingerstick testing involves
placing a drop of capillary blood on a test strip, which is Diabetic ketoacidosis (DKA) is an acute condition
then read by a glucose meter. that occurs primarily in patients with type 1 diabetes.
The three major disturbances that occur with DKA are
Most patients who develop type 2 diabetes go through hyperglycemia, metabolic acidosis, and osmotic diure-
a period of impaired glucose tolerance referred to as pre- sis. DKA typically develops over several days with
diabetes. In prediabetes, serum glucose levels are elevated symptoms such as polyuria, polydipsia, nausea, vomit-
but are not high enough to be diagnosed as diabetes. This ing, and severe fatigue, progressing to stupor and even-
condition increases the risk for developing diabetes, heart tual coma. The patient may report having abdominal
disease, and stroke. Prediabetes may result from impaired pain or tenderness, and the breath has a fruity smell as
fasting glucose or impaired glucose tolerance, or both. the lungs attempt to remove volatile ketoacids. As the
Progression from prediabetes to diabetes is not inevitable. acidosis worsens, Kussmaul’s respirations may develop,
Careful management of nutrition, regular exercise, and with an increased rate and depth of respirations. Tachy-
weight management may prevent or delay progression to cardia and hypotension occur in response to dehydra-
diabetes. Patients with prediabetes should be monitored tion and fluid depletion.
on an annual basis for the potential development of diabe-
tes and to evaluate the degree of success in managing DKA may be the first presenting symptoms of an
comorbid conditions such as HTN, hyperlipidemia, and individual previously undiagnosed with diabetes. Treat-
obesity. ment includes fluid replacement to improve circulating
blood volume and tissue perfusion, normalization of
Obesity-related insulin resistance can lead to meta- blood glucose levels, and correction of electrolyte imbal-
bolic syndrome, a cluster of biochemical changes that place ances and metabolic acidosis. Insulin therapy is begun,
the patient at increased risk for developing diabetes, heart usually with an IV loading dose, followed by a continu-
disease, peripheral vascular disease, and stroke. Again, ous low-dose infusion. Serum glucose levels must be low-
weight loss, exercise, and nutritional management enable ered gradually because too rapid a drop can cause a fluid
people with this syndrome to delay or prevent the progres- shift back into the cells that can lead to cerebral edema.
sion to type 2 diabetes. According to the American Heart Although DKA is a very serious disorder, the mortality
Association (AHA, 2016), metabolic syndrome is diag- rate for this complication has been reduced to less than
nosed by the presence of three or more of the following: 5% with proper treatment.
• Central (visceral) obesity, with waist circumference CONNECTION Checkpoint 66.1
more than 88 cm (35 in.) for women or more than
102 cm (40 in.) for men From what you learned in Chapter 33, what is the clinical defini-
tion of acidosis? What is the preferred drug for reversing metabolic
• Serum triglycerides equal to or greater than 150 mg/dL acidosis? Answers to Connection Checkpoint questions are available
• High-density lipoprotein (HDL) cholesterol less than on the faculty resources site. Please consult with your instructor.
50 mg/dL in women or less than 40 mg/dL in men (or Hyperosmolar hyperglycemic state (HHS) is a serious,
receiving drug therapy for hyperlipidemia) acute complication of diabetes that carries a mortality rate
• Blood pressure more than 130/85 mmHg (or receiving of 20% to 40%. HHS is generally seen in people with type 2
drug therapy for HTN) diabetes and is characterized by extreme hyperglycemia
• Fasting plasma glucose equal to or greater than 100 mg/dL (above 600 mg/dL), hyperosmolarity (above 310 mOsm/L)
(or receiving drug therapy for hyperglycemia). with dehydration, the absence of ketoacidosis, and central
nervous system (CNS) dysfunction. The typical patient is
Complications of Diabetes older, obese, and has comorbid medical problems, such as
Mellitus heart failure or chronic kidney disease (CKD). The ele-
vated serum glucose levels and increased osmolarity pro-
66.4 Acute complications of diabetes duce a large osmotic diuresis with marked dehydration,
include diabetic ketoacidosis, hyperosmolar confusion, and lethargy. Other possible neurologic symp-
hyperglycemic state, and hypoglycemia. toms are seizures, hemiparesis, abnormal reflexes, aphasia,
and visual disturbances. Symptoms can progress to stupor
Although most patients experience chronic diabetes, and coma. Tachycardia and hypotension result from fluid
which develops over many years, acute episodes may depletion and poor tissue perfusion. Acidosis may
occur suddenly in those with uncontrolled or poorly con- develop, caused by an accumulation of lactic acid rather
trolled diabetes. Diabetic ketoacidosis, hyperosmolar than ketoacids.
hyperglycemic state (HHS), and hypoglycemia are the
Chapter 66 Pharmacotherapy of Diabetes Mellitus 1205
The onset of HHS is gradual and, because of the neu- PROTOTYPE DRUG Glucagon (GlucaGen)
rologic manifestations, may be mistaken for a stroke in
older adults. Treatment consists of careful fluid replace- Classification Therapeutic: Antihypoglycemic drug
ment while avoiding cerebral and pulmonary edema and Pharmacologic: Pancreatic hormone
correction of electrolyte imbalances, particularly potas-
sium. Low-dose insulin is given by continuous IV infu- Therapeutic Effects and Uses: Glucagon is used
sion to slowly lower glucose levels to 250 to 300 mg/dL. for the emergency treatment of severe hypoglycemia in
Seizure precautions should be instituted, and hemody- patients with diabetes who are unconscious or unable to
namic monitoring should be used in these critically ill eat sugar or drink a sweetened beverage. It is also used
patients. The nurse should closely monitor intake and for radiographic studies to relax the smooth muscle of the
output, blood pressure, heart rate, lung sounds, weight, GI tract. GlucaGen is obtained through recombinant DNA
peripheral pulses, and neurologic status. Finally, the technology and is identical in structure to human glucagon.
underlying cause of the episode should be investigated
and treated as needed. Glucagon can be given intramuscularly (IM), subcuta-
neously, or IV. It will raise serum glucose levels in 10 to
Hypoglycemia, or abnormally low serum glucose, 20 minutes. Because glucagon raises glucose levels by stim-
occurs most often in patients improperly treated with ulating breakdown of stored glycogen, it is not effective in
insulin and may occur during therapy with some oral patients who experience hypoglycemia due to starvation,
antidiabetic drugs. The manifestations of hypoglycemia because their glycogen stores are depleted.
result from changes in mental status and by the activa-
tion of the sympathetic nervous system. Because the From 1930 to 1950, massive doses of insulin were
brain relies on a continuous supply of glucose, falling administered to agitated psychiatric patients with serious
glucose levels may lead to headache, difficulty concen- mental illnesses to induce seizures and coma, a procedure
trating, confusion, and behavioral changes, progressing called insulin shock therapy. Upon administration of glu-
to seizures and coma. The sympathetic nervous system cose or glucagon, the patient awakened in a more sedated
activation results from the body’s attempt to increase state. Although glucagon is still approved by the U.S. Food
serum glucose by the release of catecholamines (epineph- and Drug Administration (FDA) for this purpose, this
rine and norepinephrine). These catecholamines cause inhumane practice was discontinued when antipsychotic
symptoms that include tachycardia, anxiety, sweating, drugs were discovered in the 1950s.
and the constriction of surface vessels, leading to cool,
clammy skin. Acute hypoglycemia is considered a medi- Mechanism of Action: Glucagon increases glucose
cal emergency, and if prolonged or severe, can lead to levels by increasing glycogenolysis; therefore, its actions
brain damage or death. are dependent on the presence of adequate liver glycogen
stores. Glucagon stimulates the uptake of amino acids,
The symptoms of hypoglycemia may have a very rapid increases their conversion to glucose (gluconeogenesis),
onset. Patients who have had diabetes for an extended time and promotes lipolysis in the liver, with the release of fatty
may develop hypoglycemic unawareness, which is the acids and glycerol.
inability to recognize symptoms. Some drugs, such as beta-
adrenergic blockers, interfere with the sympathetic symp- Pharmacokinetics: IM, IV, subcutaneous
toms of hypoglycemia, making it more difficult for the Route(s) Easily absorbed IM
patient to recognize the condition and for the body to cor- Absorption or subcutaneous
rect the low glucose levels. Throughout plasma
Distribution Liver, plasma, and kidneys
Factors that cause hypoglycemia in patients with dia- Primary metabolism Renal and through the bile
betes include errors in insulin dosage, failure to eat at Primary excretion IV: 5–20 min; IM: 30 min;
regular intervals, increased exercise, medication adjust- Onset of action subcutaneous: 30–45 min
ments, or changes in the insulin injection site. Alcohol 1–1.5 h
consumption can lead to hypoglycemia by decreasing Duration of action
gluconeogenesis. The treatment for hypoglycemia is
always glucose, given in a concentrated source of 15 to 20 g. Adverse Effects: Glucagon is well tolerated. Adverse
This can be repeated as necessary, while taking care not to effects include nausea, vomiting, hypersensitivity reac-
overtreat the patient and cause hyperglycemia. If the indi- tions, transient changes in blood pressure (either hypo-
vidual is unconscious, or unable to swallow safely, a small tension or HTN), tachycardia, hyperglycemia, and
amount of glucose gel or spray can be administered to the hypokalemia.
buccal mucosa. Intravenous (IV) glucose is immediately
effective in treating hypoglycemia and glucagon may be Contraindications/Precautions: Glucagon is con-
administered. traindicated in patients sensitive to protein compounds, in
1206 Unit 10 Pharmacology of the Endocrine System
patients with depleted glycogen stores, or in patients with 66.5 Serious complications of chronic diabetes
insulinoma or pheochromocytoma. It is used with caution include neuropathy, nephropathy, retinopathy,
in patients with coronary artery disease because it may and vascular disease.
affect blood pressure, heart rate, and myocardial oxygen
demand. Most patients with type 2 diabetes experience no symptoms
of their illness for many years, perhaps even decades. There
Drug Interactions: Glucagon increases serum glucose may be no acute symptoms to motivate the patient to seek
and will antagonize the effects of antidiabetic drugs. Beta- medical care. However, while years may pass without symp-
adrenergic blockers will inhibit the glucose-elevating effect toms, the effects of uncontrolled blood glucose levels are
of glucagon and will also increase the risk of blood pres- progressively producing major, irreversible changes on body
sure or heart rate adverse effects associated with glucagon. systems, especially the nervous and circulatory systems.
Herbal/Food: None known.
Teaching patients about the long-term consequences of
Pregnancy: Category B. untreated diabetes can be a major challenge for the nurse.
When diagnosed at an asymptomatic stage, it is difficult to
Treatment of Overdose: An overdose can cause convince patients to make radical changes to their lifestyle
hyperglycemia, which may be treated with insulin, IV flu- and to spend money on prescriptions when they do not feel
ids, and monitoring of electrolytes. ill. Patients must clearly understand that if they delay treat-
ment until symptoms appear, it will likely be too late to pre-
Nursing Responsibilities: vent serious, chronic complications. Intensive management
of blood glucose levels has been found to dramatically reduce
• Assess the patient’s blood glucose level before, dur- the incidence of long-term complications of diabetes.
ing, and after glucagon administration.
Neuropathies are common, affecting an estimated 60%
• Reconstitute the dry powder of glucagon with the to 70% of people with diabetes. Diabetic neuropathies
diluent supplied by the manufacturer. Gently roll the affect both the somatic and autonomic nervous systems.
vial to mix the drug but do not shake the vial. If gluca- Somatic neuropathies include paresthesias, numbness, tin-
gon fails to cause a response, IV glucose must be gling and pain, motor weakness, and muscle wasting.
given. Autonomic neuropathies include postural hypotension,
altered GI functioning including gastroparesis, or gastric
• Administer supplemental oral carbohydrates once atony, diarrhea, altered genitourinary functioning with dif-
consciousness has been achieved to restore glycogen ficulty voiding or erectile dysfunction, and possible cranial
levels and prevent secondary hypoglycemia. nerve impairment. Intensive management of blood glucose
has been shown to reduce the occurrence of neuropathies.
• Instruct the patient on the proper use of the GlucaGen
emergency kit. Diabetic nephropathy is the leading cause of end-stage
renal disease, which affects patients with both type 1 and
Lifespan and Diversity Considerations: type 2 diabetes. Most commonly, the renal glomeruli are
damaged, and progressive loss of kidney function leads to
• Calculate pediatric dosages carefully. In general, chil- eventual renal failure. Comorbid conditions that put the
dren under the age of 6 require one half the adult dose. patient at high risk for nephropathy include HTN, poor
glucose control, smoking, and hyperlipidemia.
Patient and Family Education:
Diabetic retinopathy is the leading cause of acquired
• Immediately report signs of impending hypoglycemia blindness in the United States. Thirty years after the onset
such as headache, difficulty concentrating, confusion, of diabetes, almost all people with type 1 diabetes, and
seizures, palpitations, nervousness, sweating, and over 60% of those with type 2 diabetes, show some degree
cool, clammy skin to the healthcare provider. of retinopathy (Bhavsar, 2017). Regular eye examinations
are important for everyone who has diabetes.
• At the first signs of hypoglycemia, eat sugar or other
carbohydrate because this may eliminate the need to Diabetes is a major risk factor for the development of
administer glucagon. Follow any carbohydrate with a vascular disease, including premature atherosclerosis,
protein source for longer lasting effects. which leads to coronary artery disease, cerebrovascular
disease, and peripheral vascular disease. Heart disease and
• Do not mix the GlucaGen solution with the powder stroke account for about 65% of deaths in individuals with
until it is ready to be used. Discard any unused portion. diabetes. Preventive measures are directed toward reduc-
ing risk factors: control of blood pressure, smoking cessa-
• Wear a medical alert bracelet or jewelry that identifies tion, lowering of lipid levels, and optimal glucose control.
your medical condition and its treatment. In addition, antiplatelet drugs are often indicated.
Drugs Similar to Glucagon (GlucaGen)
There are no drugs similar to glucagon.
Chapter 66 Pharmacotherapy of Diabetes Mellitus 1207
Foot ulcers occur in patients with diabetes due to Insulin effect Regular Regular Regular
peripheral neuropathies and poor circulation. Neuropa- NPH
thies may impair sensation, so a small area of irritation may
go unnoticed. Vascular insufficiency and elevated glucose Breakfast Lunch Dinner Snack
levels inhibit healing of the ulcer. If the ulcer becomes
infected, it is often resistant to treatment and can ultimately
result in the need for amputation. Diabetes is the leading
cause of nontraumatic amputations.
Insulin Therapy Insulin effect Regular NPH Regular
NPH
66.6 Insulin is the cornerstone of therapy for
patients with type 1 and gestational diabetes. Breakfast Lunch Dinner Snack
Because patients with type 1 diabetes are severely deficient Insulin effect Regular NPH
in insulin production, insulin replacement therapy is
required to survive. Insulin is also required for those with Breakfast Lunch Dinner Snack
type 2 diabetes who are unable to manage their blood glu-
cose levels with diet, exercise, and oral antidiabetic drugs. Figure 66.2 Insulin regimens.
Among adults diagnosed with diabetes, 14% take only
insulin, 15% take insulin with oral antidiabetic drugs, 57% advantages, such as a more rapid onset of action (Humalog)
take oral antidiabetic drugs only, and 14% take neither or a more prolonged duration of action (Lantus). These
insulin nor antidiabetic drugs (ADA, 2015). modified forms are called insulin analogs. It is important for
nurses and patients to know the time of peak action of any
The pharmacologic goal for patients with type 1 diabetes insulin, because that is when the risk for hypoglycemic
is to administer insulin as replacement therapy in normal adverse effects is greatest. The different types of insulins
physiologic amounts. Because insulin secretion varies greatly available are listed in Table 66.2.
in response to daily activities, pharmacotherapy must be
carefully planned in conjunction with proper meal planning Doses of insulin are highly individualized for the pre-
and lifestyle habits. The desired outcome of insulin therapy is cise control of blood glucose levels in each patient. Because
to prevent the long-term consequences of diabetes by main- the GI tract destroys insulin, it must be given by injection.
taining blood glucose levels strictly within the normal range. Some patients require two or more injections daily for proper
diabetes management. For ease of administration, two dif-
The fundamental principle to remember about insulin ferent compatible types of insulin may be mixed, using a
therapy is that the right amount of insulin must be avail- standard method, to obtain the desired therapeutic effects.
able to cells when glucose is present in the blood. Adminis- Some of these combinations are marketed in cartridges con-
tering insulin when glucose is not available can lead to taining premixed solutions. A long-acting insulin may be
hypoglycemia and, possibly, coma. This situation occurs taken daily to provide a basal blood level, with a supple-
when a patient administers insulin correctly but skips a mental rapid-acting insulin given shortly before a meal.
meal. The insulin is available to cells, but glucose is not. In
another example, the patient participates in strenuous Rapid- or regular-acting insulin can be used in continuous
exercise. The insulin may have been administered on subcutaneous infusion devices, often called insulin pumps.
schedule, and food eaten, but the active muscles quickly An infusion set, which holds a syringe of the drug, delivers
use up all the glucose in the blood, and the patient becomes
hypoglycemic. Patients with diabetes who engage in com-
petitive sports need to consume food or sports drinks just
prior to and during the activity to maintain their blood glu-
cose at normal levels. The nurse plays a key role in helping
patients plan their meals, activities, and insulin dosages
correctly. Figure 66.2 illustrates the management of type 1
diabetes and correct timing of the insulin dose with meals.
Many types of insulin are available, differing in their
source, time of onset, and peak effect and duration of action.
Almost all insulin today is human insulin obtained through
recombinant DNA technology. Pharmacologists have modi-
fied human insulin to create certain pharmacokinetic
1208 Unit 10 Pharmacology of the Endocrine System
Table 66.2 Types of Insulin: Actions and Administration
Drug Action Onset Peak Duration Administration and Timing Compatibility
Can give with NPH; draw aspart up
Insulin aspart Rapid 15 min 1–3 h 3–5 h Subcutaneous: 5–10 min first, give immediately
(NovoLog) Long before meal Do not mix with any other insulin
Long Gradual 9 h To 42 h Subcutaneous: once daily, any
Insulin degludec Long time of day Do not mix with any other insulin
(Tresiba) Gradual 6–8 h To 24 h Subcutaneous: 1–2 times daily
Rapid Do not mix with any other insulin
Insulin detemir Rapid Gradual: No peak To 24 h Subcutaneous: once daily,
(Levemir) Short begins at same time each day Can give with NPH; draw glulisine up
Intermediate 1.1 h 1 h 3–4 h first, give immediately
Insulin glargine 15–30 min Subcutaneous: 15 min before Can give with NPH; draw lispro up
(Basaglar, Lantus, 0.5–1 h 3–4 h meal first, give immediately
Toujeo) 5–15 min Subcutaneous: 15 min before Can mix with NPH, sterile water,
2–4 h 5–7 h or immediately after a meal normal saline; do not mix with glargine
Insulin glulisine 30–60 min Subcutaneous: 30–60 min Can mix with aspart, lispro, reg; do
(Apidra) 4–12 h 18–24 h before meal; IV not mix with glargine
1–2 h Subcutaneous: mix (cloudy)
Insulin lispro
(Humalog)
Insulin regular
(Humulin R, Novolin R)
Isophane insulin
suspension
(Humulin N, NPH)
insulin from the pump to a needle anchored in the subcutane- Figure 66.3 Insulin pump.
ous tissue of the abdomen. The infusion set is replaced after 2
to 3 days, at which time the injection site should be moved, at Courtesy of Ace Stock Limited/Alamy Stock Photo.
least 2 inches away from the old site. Many providers recom-
mend checking blood glucose levels within 3 to 4 hours of glucagon is administered as a replacement therapy for
replacement to ensure the system is working properly. The some patients with diabetes when they are in a hypoglyce-
pump is programmed to release small subcutaneous doses of mic state and have impaired glucagon secretion.
insulin into the abdomen at predetermined intervals, with
larger boluses administered manually at mealtime if neces- Patients with diabetes who forget their insulin dose
sary. Most pumps contain an alarm that reminds patients to face equally serious consequences. Again, remember the
take their insulin. They are generally worn on a belt or tucked fundamental principle of insulin pharmacotherapy: The
into a pocket. Figure 66.3 shows an insulin pump. right amount of insulin must be available to cells when
glucose is present in the blood. Without insulin present,
The primary adverse effect of insulin therapy is over- glucose from a meal can build up to high levels in the blood,
treatment; insulin may remove too much glucose from the causing hyperglycemia and possible coma. Proper planning
blood, resulting in hypoglycemia. This may occur when a and teaching by the nurse are essential to achieve successful
patient with type 1 diabetes has more insulin in the blood outcomes and maximize patient adherence with therapy.
than is needed to balance the amount of circulating blood glu-
cose. Hypoglycemia may occur when the insulin level peaks,
during exercise, when the patient receives too much insulin
due to a medication error, or if the patient skips a meal. Some
of the symptoms of hypoglycemia are the same as those of
DKA. Those that differ and help to determine that a patient is
hypoglycemic include pale, cool, and moist skin, with blood
glucose less than 50 mg/dL and a sudden onset of symptoms.
Left untreated, severe hypoglycemia may result in death.
Other adverse effects of insulin include injection-site
reactions, generalized urticaria, and swollen lymph glands.
Some patients will experience Somogyi phenomenon, a
rapid decrease in blood glucose, usually during the night,
which stimulates the release of hormones that elevate
blood glucose (epinephrine, cortisol, and glucagon), result-
ing in an elevated morning blood glucose level. Adminis-
tration of insulin above the patient’s normal dose may
produce a rapid rebound hypoglycemia. The hormone
Chapter 66 Pharmacotherapy of Diabetes Mellitus 1209
Insulin Adjunct Mechanism of Action: Regular insulin is identical to
endogenous insulin. Insulin decreases blood glucose levels by
Pramlintide (Symlin) is an antihyperglycemic drug approved increasing cellular uptake of glucose and stimulating storage
in 2005 that is used along with insulin in patients with type 1 of glucose as glycogen; it also inhibits the release of glucagon.
or type 2 diabetes who are not able to achieve glucose con-
trol by the use of insulin alone. The drug is a synthetic ana- Pharmacokinetics:
log of amylin, a natural hormone released by the beta cells of
the pancreas at the same time as insulin. Its natural function Route(s) Subcutaneous; IV (only regular
is to act synergistically with insulin in glycemic control. The
therapeutic actions of pramlintide are to slow gastric empty- insulin can be given IV); inhalation
ing time, reduce postprandial glucagon secretion, and
increase satiety, thereby leading to reduced calorie intake. Absorption Rapidly absorbed following
Pramlintide is administered subcutaneously immediately subcutaneous injection; absorption
prior to major meals using a premeasured disposable injec-
tor called a SymlinPen. It cannot be mixed with insulin, and time can vary by site of injection
it must be injected into a different site than insulin. When ini-
tiating treatment, rapid- or short-acting insulin doses are Distribution Throughout extracellular fluids
usually reduced by 50%. Adverse effects include nausea,
vomiting, abdominal pain, headache, dizziness, fatigue, Primary metabolism Hepatic
coughing, allergic reaction, or arthralgia. The drug carries a
black box warning that severe hypoglycemia may occur dur- Primary excretion Liver and kidneys
ing therapy. Hypoglycemia may be prolonged and severe,
usually occurring within 3 hours following an injection. Onset of action Subcutaneous: 30–60 min; IV:
15 min
PROTOTYPE DRUG Human Regular Insulin
(Humulin R, Novolin R) Duration of action 6–10 h
Classification Therapeutic: Antidiabetic drug, pancreatic Adverse Effects: The most common adverse effect of
hormone insulin therapy is hypoglycemia. Rebound hyperglycemia
(Somogyi phenomenon) may occur. Irritation at injection
Pharmacologic: Short-acting sites may occur, including lipohypertrophy, the accumula-
hypoglycemic drug tion of fat in the area of injection. This effect is lessened
with rotation of injection sites. Weight gain is a possible
Therapeutic Effects and Uses: Human regular insu- adverse effect. Because insulin facilitates the intracellular
lin is used to maintain blood glucose levels within normal uptake of potassium, hypokalemia is possible.
limits. The primary effects of human regular insulin are
promotion of cellular uptake of glucose, amino acids, and Contraindications/Precautions: Insulin is used
potassium; promotion of protein synthesis, glycogen for- with caution in pregnancy, CKD, fever, and thyroid dis-
mation and storage, and fatty acid storage as triglycerides; ease and among infants, children, and older adults. Insulin
and conservation of energy stores by promoting the utili- should not be administered to patients with hypoglyce-
zation of glucose for energy needs and inhibiting gluco- mia. Patients with hypokalemia should be monitored care-
neogenesis. Indications for insulin include the following: fully because insulin may worsen this condition.
• As monotherapy to lower blood glucose levels in Drug Interactions: Caution must be used when insu-
patients with type 1 diabetes lin is concurrently administered with drugs that can pro-
duce hypoglycemia, including sulfonylureas, meglitinides,
• In combination with oral antidiabetic drugs in patients beta-adrenergic blockers, salicylates, anabolic steroids,
with type 2 diabetes monamine oxidase inhibitors (MAOIs), and alcohol. Sev-
eral drugs can antagonize the glucose-lowering effects of
• For the emergency treatment of DKA or hyperosmolar insulin including dextrothyroxine, corticosteroids, epi-
hyperglycemic state nephrine or norepinephrine, furosemide, and thiazide
diuretics. Angiotensin-converting enzyme (ACE) inhibitors
• For gestational diabetes. increase insulin sensitivity and may enhance the hypogly-
cemic effects of insulin. Many other drugs can influence
Because regular insulin is short acting, it is most often blood glucose and the nurse should consult current drug
used in combination with intermediate- or long-acting references when treating patients who take high insulin
insulin to achieve 24-hour glucose control. Nondiabetic doses or who have unstable diabetes. Herbal/Food: Garlic,
indications for insulin include stimulation of growth hor- chromium, black cohosh, bitter melon, bilberry, and gin-
mone secretion in the evaluation of growth hormone defi- seng may potentiate the hypoglycemic effects of insulin.
ciency and the treatment of hyperkalemia to promote a Cocoa and rosemary may have a hyperglycemic effect.
shift of potassium into cells.
Pregnancy: Insulin glargine is pregnancy category C;
other forms of insulin are category B.
Treatment of Overdose: An overdose of insulin can
cause profound hypoglycemia, which is treated with a
1210 Unit 10 Pharmacology of the Endocrine System
concentrated source of glucose (dextrose), such as D5W or patient. At low doses (0.2 unit/kg), effects persist about
glucagon, by the parenteral route. 12 hours. At higher doses (0.4 unit/kg), effects last 20 to
24 hours. Because of its slow onset and prolonged dura-
Nursing Responsibilities: Key nursing implications tion, insulin detemir is used to provide basal glycemic con-
for patients receiving regular insulin are included in the trol. It is not injected before meals to control postprandial
Nursing Practice Application for Patients Receiving Phar- hyperglycemia. It cannot be mixed with any other type of
macotherapy with Insulin. insulin and is only given by subcutaneous injection. Insu-
lin detemir is supplied in 10-mL vials, 3-mL cartridges, a
Drugs Similar to Human Regular Insulin 3-mL pen, and a 3-mL InnoLet dosing device. The InnoLet
(Humulin R, Novolin R) dosing injection device is disposable and has an easy-to-
read dial, large push button for injection, and audible
Many types of insulin are available. They are categorized clicks that indicate each unit injected.
by their onset of action and duration of action, as given in
Table 66.2. Premixed formulations of insulin, such as Insulin glargine (Basaglar, Lantus, Toujeo): Insulin
Humulin 70/30, are also available. This type contains glargine is a recombinant insulin analog that exhibits con-
70% NPH insulin and 30% regular insulin, so it can be given stant, long-duration insulin activity. It has no defined peak
before a meal to help control postprandial glucose while effect and provides for the maintenance of steady blood
also providing longer coverage of insulin needs. Other levels, leading to a lowered risk of hypoglycemia. Insulin
combination insulins include Humalog 75/25, Humulin glargine allows for once-daily dosing as basal insulin cov-
50/50, Novolin 70/30, and NovoLog 70/30. The characteris- erage. Although it can be given without regard to meals, it
tics of selected insulin combinations are shown in Table 66.3. should be given at the same time each day to provide con-
sistent blood levels. It cannot be mixed with any other type
Insulin aspart (NovoLog): Insulin aspart is a rapid-onset of insulin and is only given by subcutaneous injection.
drug, with a structure very similar to that of endogenous Insulin glargine may also help improve the lipid profiles
insulin. Insulin aspart has a more rapid onset of action and A1C levels of type 2 diabetes when added to therapy.
than regular insulin, acting within about 15 minutes when
given subcutaneously. Because insulin aspart acts rapidly, Insulin glulisine (Apidra): Insulin glulisine has a 10- to
injections should be made 5 to 10 minutes before meals. It 15-minute onset and a short duration of 3 to 5 hours.
also has a short duration of action, 3 to 5 hours when com- Because of its rapid onset, the drug should be adminis-
pared to regular insulin. Because of its short duration, tered no sooner than 15 minutes before eating and no later
insulin aspart is usually given in combination with an than 20 minutes after starting a meal. Apidra is given only
intermediate- or long-acting form of insulin. Insulin aspart by subcutaneous injection.
is available in 10-mL vials and 3-mL prefilled cartridges.
Insulin lispro (Humalog): Insulin lispro is a rapid-acting
Insulin degludec (Tresiba): Insulin degludec is a newer analog of regular insulin, with effects beginning within 15 to
long-acting insulin analog approved in 2015 for both type 30 minutes of subcutaneous injection. Insulin lispro acts
1 and type 2 diabetes. Because it has a long duration of up faster than regular insulin but has a shorter duration of
to 42 hours, it may be taken at any time of day, regardless action, 5 hours or less. Because of its rapid onset, insulin lis-
of meals. It is administered by the subcutaneous route. pro should be administered immediately before eating, or
Ryzodeg 70/30 is a mixture of insulin degludec and insu- shortly after eating. It is intended to help control the rise in
lin aspart, a rapid-acting human insulin analog. blood glucose brought on by a meal and is normally given
concurrently with an intermediate- or long-acting drug that
Insulin detemir (Levemir): Insulin detemir is a long- provides a basal coverage of insulin. It is a clear insulin and
acting insulin with a slow onset and dose-dependent dura- does not require mixing prior to injecting. Lispro is often
tion of action. Detemir may be given once or twice a day, used with insulin infusion pumps and cannot be given IV.
depending on the dose, which is individualized to the
Table 66.3 Premixed Insulin Combinations
Drug Description Onset (min) Peak (h) Duration (h) Adverse Effects
Humalog Mix 75/25 75% insulin lispro protamine/ 25% insulin lispro 15–60 1–6.5 Up to 24
Humulin 50/50 50% NPH insulin/ 50% regular insulin 30–60 2–5.5 Up to 24 Pain and swelling at
Humulin 70/30 70% NPH insulin/30% regular insulin 30–60 1.5–16 Up to 36 injection site
Novolin 70/30 70% NPH insulin/ 30% regular insulin 30–60 2–12 Up to 36 Hypoglycemia, DKA
NovoLog Mix 70/30 70% insulin aspart protamine/ 30% insulin aspart 15–60 1–4 Up to 24
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
Chapter 66 Pharmacotherapy of Diabetes Mellitus 1211
Isophane insulin (Humulin N, NPH): Isophane insulin is neutral protamine Hagedorn. Hans Christian Hagedorn
the only intermediate-acting insulin. It has a slower onset was a scientist who developed the drug in the 1920s.
of action (1 to 4 hours) than regular insulin and a duration
of action of up to 18 to 24 hours. It is used to provide a basal Antidiabetic Drugs for Type 2
level of insulin coverage between meals and at night. NPH Diabetes
insulin is normally administered 30 minutes before the first
meal of the day, but in some instances a second, smaller 66.7 Antidiabetic drugs from multiple classes
dose is taken before the evening meal or at bedtime. Many are used to treat type 2 diabetes.
patients are prescribed insulin that is premixed, such as
70% NPH with 30% regular or rapid acting. NPH is a The six primary classes of antidiabetic drugs used to treat
cloudy suspension and requires mixing prior to drawing type 2 diabetes are differentiated by their chemical structures
up a dose. NPH can be given with aspart, lispro, or regular and their mechanisms of action. Drug classes prescribed for
insulin, but it cannot be mixed with glargine insulin. When patients with type 2 diabetes include alpha-glucosidase
mixed with another type of insulin, NPH should be drawn inhibitors, biguanides, incretin enhancers, meglitinides, sul-
up after the other insulin, and the mixture should be fonylureas, and thiazolidinediones. An additional group
administered immediately. The term NPH stands for includes miscellaneous drugs from other classes. All the
CONNECTIONS: Lifespan Considerations
Diabetes in the School Setting
Caring for the school-age child with diabetes in a school setting • Information on meals and snacks, including scheduling, the
requires teamwork among the parents or caregiver, school nurse, need for the child to be able to eat prn (as needed) to prevent
school staff, the child’s healthcare provider, and, most often, the hypoglycemia, and content and calories of a school lunch.
child. For each child, an individual diabetes medical management
plan (DMMP) should be established that addresses all aspects of • Symptoms and treatment for hypoglycemia and hyperglyce-
the diabetes care. The ADA (2014) recommends the following mia. Specific levels of training should be provided to school
specific instructions be included in each child’s DMMP: personnel based on whether they will administer basic, inter-
mediate, or advanced treatment in caring for the child.
• Blood glucose monitoring instructions, including the fre-
quency and circumstances for requiring monitoring. Provi- • Information on participation in physical activity.
sion should be made for privacy during testing or insulin • Emergency plans for emergency evacuation, shelter-in-
administration if the child, parents, or caregiver desires.
place, or school lockdowns.
• Information on insulin injections, if used, to include type(s) of
insulin, dose, times for administration, storage, and provider By establishing a DMMP, routine daily care as well as emer-
permission for adjustments in insulin dosage if needed. gency contingencies can be addressed. When all participants
work as a team, a child with diabetes can participate fully and
safely in the school setting.
CONNECTIONS: NURSING PRACTICE APPLICATION
Patients Receiving Pharmacotherapy with Insulin
Assessment
Baseline assessment prior to administration:
• Obtain a complete health history including endocrine, cardiovascular, hepatic, or kidney disease; pregnancy; or breastfeeding. Obtain a drug history
including allergies, current prescription and over-the-counter (OTC) drugs, herbal preparations, caffeine, nicotine, and alcohol use. Be alert to possible
drug interactions.
• Obtain a history of current symptoms, duration and severity, and other related signs or symptoms (e.g., paresthesias of hands or feet). Assess feet and
lower extremities for possible injury, infection, or ulcerations.
• Obtain a dietary history including caloric intake if on an ADA diet, number of meals and snacks per day. Assess fluid intake and type of fluids consumed.
• Obtain baseline vital signs, height, and weight.
• Evaluate appropriate laboratory findings (e.g., complete blood count [CBC], electrolytes, glucose, A1C level, lipid profile, osmolality, and hepatic and
renal function studies).
• Assess the patient’s ability to receive and understand instructions. Include family and caregivers as needed.
Assessment throughout administration:
• Assess for desired therapeutic effects (e.g., glucose levels remain within normal limits, electrolytes and osmolality remain normal, A1C level
demonstrates adequate glucose control).
• Assess for and report promptly any adverse effects: signs of hypoglycemia (e.g., nausea, paleness, sweating, diaphoresis, tremors, irritability,
headache, light-headedness, anxiety, decreased level of consciousness) and hyperglycemia (e.g., flushed, dry skin, polyuria, polyphagia, polydipsia,
drowsiness, glycosuria, ketonuria, acetone-breath), lipodystrophy, infection.
(continued )
1212 Unit 10 Pharmacology of the Endocrine System
CONNECTIONS: NURSING PRACTICE APPLICATION (continued)
Implementation
Interventions and (Rationales) Patient-Centered Care
Ensuring therapeutic effects: • Teach the patient to report any return of original symptoms.
• Continue assessments as above for therapeutic effects. (Depending on • Teach the patient the symptoms of hyper- and hypoglycemia to observe
the severity of hyperglycemia, blood glucose levels should return for and instruct the patient to check the capillary glucose level routinely
gradually to normal.) and if symptoms are present. Promptly report any noticeable symptoms
and concurrent capillary glucose level to the healthcare provider.
• Administer insulin correctly and per the schedule ordered (e.g., routine • Teach the patient, family, or caregiver appropriate administration
dosing with or without additional sliding-scale coverage). Plan insulin techniques for all types of insulin used, followed by return
administration and peak times around mealtimes. (Maintaining a steady demonstration until the patient or caregiver is comfortable with the
level of insulin with mealtimes arranged to match peak insulin activity technique and able to perform correctly.
will assist in maintaining a steady blood glucose level.)
• Teach the patient, family, or caregiver the importance of peak insulin
levels and the need to ensure that adequate food sources are
consumed to avoid hypoglycemia. Provide written materials for future
reference whenever possible.
• Ensure that dietary needs are met based on the need to lose, gain, or • Review current diet, lifestyle, and activity level with the patient. Arrange
maintain current weight and glucose levels. Consult with the dietitian a dietitian consult based on the need to alter diet or food choices.
as needed. Limit or eliminate alcohol use. (Adequate caloric, protein, Teach the patient to limit or eliminate alcohol use. If alcoholic
carbohydrate, and fat amounts support an insulin regimen for glucose beverages are consumed, limit to one per day, and consume along
control. Activity and lifestyle will also be factored into dietary with a complete meal to ensure that food intake balances alcohol
management. As alcohol is metabolized, it can raise and then metabolism.
precipitously lower blood sugar, increasing the risk of hypoglycemia.)
Minimizing adverse effects: • Instruct the patient on blood glucose monitoring the appropriate
• Continue to monitor capillary glucose levels. Hold insulin dose if blood techniques to obtain capillary blood glucose levels, followed by return
demonstration, and when to contact the healthcare provider (e.g.,
sugar is less than 70 mg/dL or per parameters as ordered, and contact glucose less than 70 mg/dL). Monitor use and ensure proper
the healthcare provider for further orders. (Daily glucose levels, functioning of all equipment to be used at home.
especially before meals, will assist in maintaining adequate control of
blood glucose and aid in assessing the appropriateness of current
insulin types and dosages.)
• Continue to monitor periodic laboratory work: CBC, electrolytes, • Instruct the patient on the need to return periodically for laboratory
glucose, A1C level, lipid profile, osmolality, hepatic and renal function work.
studies. (Periodic monitoring of laboratory work assists in determining
glucose control and the need for any change in insulin amounts and
assesses for complications. A1C level provides a measure of glucose
control over several months’ time.)
• Assess for symptoms of hypoglycemia, especially around the time of • Teach the patient to always carry a quick-acting carbohydrate source
insulin peak activity. If symptoms of hypoglycemia are noted, provide a in case symptoms of hypoglycemia occur. If unsure whether symptoms
quick-acting carbohydrate source (e.g., juice or other simple sugar), indicate hypo- or hyperglycemia, treat as hypoglycemia and then
and then check capillary glucose level. Report to the healthcare check capillary glucose. If symptoms are not relieved in 10–15 min, or
provider if glucose is less than 70 mg/dL or as ordered. If mealtime is if blood sugar is below 70 mg/dL (or parameters as ordered),
not immediate, provide a longer acting protein source to ensure that immediately notify the healthcare provider.
hypoglycemia does not recur. (Hypoglycemia is especially likely to
occur around peak insulin activity, especially if food sources are
inadequate. Lifespan: Age-related physiologic differences may place
the older adult at greater risk for hypoglycemia. Providing a quick-
acting carbohydrate source and then checking the capillary glucose
level will ensure that glucose does not decrease further while locating
the glucose testing equipment. When in doubt, treating symptoms for
suspected hypoglycemia is safer than allowing further decreases in
glucose and possible loss of consciousness with adverse effects.
Small additional amounts of carbohydrates will not dramatically
increase blood sugar if testing shows a hyperglycemic episode.)
• Monitor blood glucose more frequently during periods of illness or • Instruct the patient to check glucose levels more frequently when ill or
stress. (Insulin needs may increase or decrease during periods of under stress. Stress may increase insulin needs because the stress
illness or stress. Frequent monitoring during these times helps to response can cause glycogenolysis. Illness, especially associated with
prevent hypoglycemia and ensures adequate glucose control.) anorexia, nausea, or vomiting, may decrease insulin needs. Notify the
healthcare provider if unable to eat normal meals during periods of
illness or stress for possible change in insulin dose.
• Encourage increased activity and exercise, but monitor blood glucose • Teach the patient the benefits of increased activity and exercise and to
before and after exercise and begin any new or increased exercise begin any new routine or increase in exercise gradually. Exercise
routine gradually. Continue to monitor for hypoglycemia for up to 48 h should occur an hour after a meal or after a 10- or 15-g carbohydrate
after exercise. (Exercise assists muscles to use glucose more efficiently snack to prevent hypoglycemia. If exercise is prolonged, small frequent
and increases insulin receptor sites in the tissues, lowering the blood carbohydrate snacks can be consumed every 30 min during exercise
sugar. Benefits of exercise and lowered blood sugar may continue for to maintain blood sugar.
up to 48 h, increasing the risk of hypoglycemia during this time.
Frequent monitoring helps to prevent hypoglycemia and ensures • Instruct the patient to check glucose levels more frequently before,
adequate glucose control.) during, and after exercise.
Chapter 66 Pharmacotherapy of Diabetes Mellitus 1213
CONNECTIONS: NURSING PRACTICE APPLICATION (continued)
Implementation
Interventions and (Rationales) Patient-Centered Care
• Rotate insulin administration sites weekly. If the patient is hospitalized, • Instruct the patient on the need to rotate insulin injection sites on a
use sites that have been less used or are difficult for the patient to weekly basis to prevent tissue damage or to rotate subcutaneous
reach. Insulin pump subcutaneous catheters should be changed every catheter sites (insulin pumps) every 2–3 days.
2–3 days or as recommended by the healthcare provider. (Rotating
injection sites weekly helps to prevent lipodystrophy. Use caution if
using a new site, especially if the previous site used by the patient
exhibits signs of lipodystrophy. Insulin in an unused site may absorb
more quickly than in a site with lipodystrophy or tissue changes,
resulting in hypoglycemia. Insulin pump subcutaneous catheters should
be changed every 2–3 days to prevent infections at the site of insertion.)
• Ensure proper storage of insulin to maintain maximum potency. • Teach the patient methods for proper storage of insulin and for storage
(Unopened insulin may be stored at room temperature, but avoid direct during travel.
sunlight and excessive heat. Opened insulin vials may be stored at
room temperature for up to 1 month. If noticeable change in solution
occurs or if precipitate forms, discard the vial.)
Patient understanding of drug therapy: • The patient, family, or caregiver should be able to state the reason for
• Use opportunities during administration of medications and during the drug, appropriate dose and scheduling, what adverse effects to
observe for and when to report them, and any special requirements of
assessments to discuss the rationale for drug therapy, desired the medication therapy (e.g., insulin needs during exercise or illness).
therapeutic outcomes, commonly observed adverse effects,
parameters for when to call the healthcare provider, and any necessary • Instruct the patient to carry a wallet identification card and wear
monitoring or precautions. (Using time during nursing care helps to medical identification jewelry indicating diabetes.
optimize and reinforce key teaching areas.)
Patient self-administration of drug therapy: • The patient, family, or caregiver is able to discuss appropriate dosing
• When administering the medication, instruct the patient, family, or and administration needs including:
• Proper preparation of insulin: Rotate vials gently between the palms
caregiver in the proper self-administration of the drug followed by and do not shake; if insulins are mixed, draw up the quickest acting
teach-back. (Utilizing time during nurse administration of these drugs insulin and then the longer acting one if insulins are compatible;
helps to reinforce teaching.) insulin glargine or insulin detemir should not be mixed with any
other type of insulin; use the appropriate syringe (100 unit) unless
small amounts of insulin are ordered, then obtain syringes with
smaller volumes to ensure accurate dosing.
• Proper subcutaneous injection techniques: selection and cleansing
of the site with rotation every week, injecting at 90-deg angle, and
applying a pad to the site after injection but not massaging the site.
• Proper use of all equipment: blood glucose monitoring equipment,
insulin pump.
CONNECTIONS: Patient Safety College of Endocrinology (2015) are designed to target an A1C
level of 6.5% or less with an FPG of less than 110 g/dL. In gen-
Incorrect Insulin Dose eral, all of the antidiabetic drugs are similar in their ability to
lower A1C levels in the short term. There are some differences,
A patient with diabetes has 30 units of Humulin R (regular) however, in long-term control. For example, drugs in the thia-
insulin ordered for the morning dose. There are several patients zolidinedione class appear to maintain glycemic control for
with diabetes on the unit and the nurse has given many doses 5 to 6 years, while the sulfonylureas peak at 6 months and
of insulin that morning. The nurse prepares the insulin but slowly decline in efficacy. The adverse effects observed for
draws up Humalog 30 units instead. The patient begins expe- each class differ: Some cause hypoglycemia, whereas others
riencing symptoms of hypoglycemia within 15 minutes and is cause weight gain or GI complaints such as diarrhea. Because
treated successfully. there is no perfect drug for type 2 diabetes, choice of therapy is
guided by the experiences of the prescriber and the results
What errors occurred and how could they be prevented achieved by the individual patient. A comparison of the anti-
in the future? diabetic drug classes is presented in Table 66.4. Doses of the
individual medications are listed in Table 66.5.
Answers to Patient Safety questions are available on the faculty
resources site. Please consult with your instructor. Therapy for type 2 diabetes is usually initiated with a
single drug. The AACE recommends metformin as the ini-
medications used to treat type 2 diabetes require some tial therapy for most patients with type 2 diabetes (AACE &
degree of pancreatic insulin secretion. These antidiabetic American College of Endocrinology, 2015). If glycemic con-
medications are not effective in treating type 1 diabetes trol is not achieved with monotherapy, a second medication
because these patients have a total lack of insulin secretion. is added to the therapeutic regimen. Failure to achieve
Treatment goals recommended by the American Associa-
tion of Clinical Endocrinologists (AACE) and the American
1214 Unit 10 Pharmacology of the Endocrine System
Table 66.4 Summary of Antidiabetic Drug Classes
Drug Action(s) Nursing Considerations
Alpha-Glucosidase Interfere with carbohydrate breakdown and absorption; act locally in Common GI effects; hypoglycemia can occur if combined
Inhibitors the GI tract with little systemic absorption with another oral drug; if this occurs, treat with glucose, not
sucrose; take with meals
Biguanides Decrease production and release of glucose from the liver; increase
cellular uptake of glucose; lower lipid levels; promote weight loss Common GI adverse effects; risk for lactic acidosis (rare);
Incretin Enhancers Slow the breakdown of insulin, keeping it circulating in the blood avoid alcohol; low risk for hypoglycemia
longer; slow the rate of digestion, which increases satiety
Well tolerated; minor nausea, vomiting, and diarrhea; some
weight loss is likely; low risk for hypoglycemia
Meglitinides Stimulate insulin release Can cause hypoglycemia, GI effects; well tolerated;
administer shortly before meals
Sulfonylureas Stimulate insulin release; decrease insulin resistance Can cause hypoglycemia, GI disturbances, rash; cross
sensitivity with sulfa drugs and thiazide diuretics; possible
disulfiram response with alcohol
Thiazolidinediones Decrease production and release of glucose from the liver; increase Can cause fluid retention and worsening of heart failure;
insulin sensitivity in fat and muscle tissue therapeutic effects take several weeks to develop
Table 66.5 Antidiabetic Drugs for Type 2 Diabetes
Drug Route and Adult Dose (Maximum Dose Where Indicated) Adverse Effects
Alpha-Glucosidase Inhibitors
acarbose (Precose) PO: 25–100 mg tid (max: 300 mg/day) Flatulence, diarrhea, abdominal distention
miglitol (Glyset) PO: 25–100 mg tid (max: 300 mg/day) Hypoglycemia (tremors, palpitations, sweating)
Biguanide
metformin immediate release PO: 500 mg bid or 850 mg once daily; increase to 1000–2550 mg in 2–3 Flatulence, diarrhea, nausea, anorexia,
(Glucophage, Riomet) divided doses/day (max: 2.55 g/day) abdominal pain, bitter or metallic taste,
decreased vitamin B12 levels
extended release (Fortamet, Glumetza: 1000–2000 mg once daily (max: 2 g/day)
Glucophage XR, Glumetza) Lactic acidosis
Glucophage XR: 500 mg once daily (max 2 g/day)
Fortamet: 1000 mg once daily (max: 2.5 g/day)
Incretin Mimetics (GLP-1 Receptor Agonists)
albiglutide (Tanzeum) Subcutaneous: 30–50 mg once weekly Nausea, vomiting, diarrhea, headache,
dulaglutide (Trulicity) Subcutaneous: 0.75–1.5 mg once weekly nervousness
exenatide (Byetta) Subcutaneous: 5–10 mcg bid 60 min prior to morning and evening meals
liraglutide (Victoza) Subcutaneous: 0.6–1.8 mg once daily, any time of day Hypoglycemia (tremors, palpitations, sweating),
lixisenatide (Adlyxin) Subcutaneous: 10–20 mcg once daily prior to morning meal antibody formation, pancreatitis, CKD
(exenatide), thyroid tumors (liraglutide,
albiglutide)
Incretin Enhancers (DPP-4 Inhibitors)
alogliptin (Nesina) PO: 25 mg once daily Headache, upper respiratory and urinary tract
linagliptin (Tradjenta) PO: 5 mg once daily infections
saxagliptin (Onglyza) PO: 2.5–5 mg once daily
sitagliptin (Januvia) PO: 100 mg once daily Hypoglycemia (tremors, palpitations, sweating),
anaphylaxis, peripheral edema, exfoliative
dermatitis, Stevens–Johnson syndrome
Meglitinides
nateglinide (Starlix) PO: 60–120 mg tid, 1–30 min prior to meals Flulike symptoms, upper respiratory infection,
repaglinide (Prandin) PO: 0.5–4 mg bid–qid, 1–30 min prior to meals (max: 16 mg/day) back pain
Hypoglycemia (tremors, palpitations, sweating),
anaphylaxis, pancreatitis
Sulfonylureas, First Generation
chlorpropamide (Diabinese) PO: 100–500 mg/day (max: 750 mg/day) Nausea, heartburn, dizziness, headache, drowsiness
tolazamide (Tolinase) PO: 100–500 mg 1–2 times/day (max: 1 g/day)
tolbutamide (Orinase) PO: 250–1500 mg 1–2 times/day (max: 3 g/day) Hypoglycemia (tremors, palpitations, sweating),
cholestatic jaundice, blood dyscrasias
Sulfonylureas, Second Generation
glimepiride (Amaryl) PO: 1–4 mg/day (max: 8 mg/day) Nausea, heartburn, dizziness, headache, drowsiness
glipizide (Glucotrol) PO: 2.5–20 mg 1–2 times/day (max: 40 mg/day)
glyburide (DiaBeta) PO: 1.25–10 mg 1–2 times/day (max: 20 mg/day) Hypoglycemia (tremors, palpitations, sweating),
glyburide micronized (Glynase) PO: 0.75–12 mg 1–2 times/day (max: 12 mg/day) cholestatic jaundice, blood dyscrasias
Chapter 66 Pharmacotherapy of Diabetes Mellitus 1215
Table 66.5 Antidiabetic Drugs for Type 2 Diabetes (continued)
Drug Route and Adult Dose (Maximum Dose Where Indicated) Adverse Effects
Thiazolidinediones
pioglitazone (Actos) PO: 15–30 mg/day (max: 45 mg/day) Upper respiratory infection, myalgia, headache,
rosiglitazone (Avandia) PO: 4–8 mg 1–2 times/day (max: 8 mg/day) edema, weight gain
Hypoglycemia (tremors, palpitations, sweating),
Miscellaneous Drugs PO: 0.8–4.8 mg/day upon awakening hepatotoxicity, bone fractures, heart failure, MI
bromocriptine (Cycloset)
Nausea, fatigue, dizziness, vomiting, and headache
canagliflozin (Invokana) PO: 100 mg once daily (max: 300 mg/day) taken before first meal Hypotension, psychosis, drowsiness
dapagliflozin (Farxiga) PO: 5–10 mg once daily in the morning, with or without food Female genital mycotic infections, urinary tract
empagliflozin (Jardiance) PO: 10–25 mg once daily in the morning, with or without food infection, and nasopharyngitis
Hypotension, CKD, hyperkalemia, hypoglycemia
Note: Italics indicate common adverse effects. Underline indicates serious adverse effects.
glycemic control with two oral hypoglycemic drugs sug- effect is hypoglycemia, which is usually caused by taking too
gests the need for insulin to be added to the regimen. much medication or not eating enough food. Hypoglycemia
from these drugs may be prolonged and require administration
Many fixed-dose combination products are available for of dextrose to return serum glucose to normal levels. Other
the treatment of people with type 2 diabetes. The main adverse effects include weight gain, hypersensitivity reactions,
advantage of taking a combination drug is that it is more GI distress, and hepatotoxicity. When alcohol is taken with sul-
convenient than taking two separate drugs and may improve fonylureas, some patients experience an uncomfortable disulfi-
adherence to the therapeutic regimen. Combination prod- ram-like reaction, with flushing, palpitations, and nausea.
ucts are indicated for patients who fail to adequately control
glucose levels with the use of a single drug. Doses for PROTOTYPE DRUG Glyburide (DiaBeta, Glynase)
selected combination products are listed in Table 66.6.
Sulfonylureas Classification Therapeutic: Antidiabetic drug
Pharmacologic: Sulfonylurea
The first oral antidiabetic drug class available, sulfonyl-
ureas are divided into first- and second-generation catego- Therapeutic Effects and Uses: Approved in 1984,
ries. Although drugs from both generations are equally glyburide is a second-generation sulfonylurea used to
effective at lowering blood glucose, the second-generation lower blood glucose levels in patients with type 2 diabetes.
drugs exhibit fewer drug–drug interactions. Glyburide can be used alone or in combination with
another oral hypoglycemic drug. It should be used only if
The sulfonylureas act by stimulating the release of insulin diet and exercise have proven ineffective in controlling the
from pancreatic islet cells and by increasing the sensitivity of elevated blood glucose levels.
insulin receptors on target cells. The most common adverse
Table 66.6 Selected Combination Oral Antidiabetic Drugs*
Trade-Name Drug Generic Drug Combination Route and Adult Dose (Maximum Dose Where Indicated)
Actoplus Met pioglitazone/metformin
Avandamet rosiglitazone/metformin PO: 15 mg/500–850 mg bid (regular release) or 15–30 mg/1000 mg once daily (extended release)
Duetact pioglitazone/glimepiride
Glucovance glyburide/metformin PO: 4 mg/1000 mg daily in divided doses
Janumet sitagliptin/metformin
PO: Start with 30 mg/2 mg once daily (max: 45 mg/8 mg daily)
Jentadueto linagliptin/metformin
PO: 1.25–5 mg/250–500 mg once or twice daily with a meal (max: 20 mg/2000 mg daily)
Kazano alogliptin/metformin
Oseni alogliptin/pioglitazone PO: Starting dose 50 mg/500 mg bid (regular release) or 100 mg/1000 mg once daily
PrandiMet repaglinide/metformin (extended release) (max: 100 mg/2000 mg/day)
Qtern dapagliflozin/saxagliptin
Synjardy empagliflozin/metformin PO: 2.5 mg/500–1000 mg bid (regular release) or 5 mg/1000 mg once daily (extended release)
with meals
PO: 12.5 mg/500 mg bid with meal
PO: 25 mg/15 mg once daily with or without food
PO: 1 mg/500 mg bid, 15 min before meals (max: 10 mg/2500 mg daily)
PO: 10 mg/5 mg once daily with morning meal
PO: 12.5 mg/1000 mg bid with meals (regular release) or 25 mg/2000 mg once daily with
morning meal (extended release)
* Dosage levels are determined individually according to patient response and glycemic laboratory results.
1216 Unit 10 Pharmacology of the Endocrine System
Two types of glyburide are available: the conventional anticoagulants, MAOIs, probenecid, sulfonamides, chlor-
form (DiaBeta) and a micronized form (Glynase). Glynase amphenicol, oxyphenbutazone, phenylbutazone, salicy-
allows for lower doses, compared to the conventional lates, and clofibrate. Increased risk of hyperglycemia can
forms. Glucovance is a combination product that contains occur with use of rifampin and thiazides. Herbal/Food:
glyburide and metformin. Ginseng, garlic, black cohosh, juniper berries, fenugreek,
coriander, or dandelion root can cause hypoglycemia.
Mechanism of Action: Glyburide stimulates the
release of insulin from pancreatic beta cells and increases Pregnancy: Category C.
the sensitivity of peripheral tissues to insulin. The stimu-
lation of insulin release relies on some residual beta cell Treatment of Overdose: Treatment is the same as for
functioning; therefore, the drug is not effective for type 1 acute hypoglycemia: A concentrated source of glucose is
diabetes. administered.
Pharmacokinetics: Nursing Responsibilities: Key nursing implications
for patients receiving glyburide are included in the Nursing
Route(s) Oral (PO) Practice Application for Patients Receiving Pharmacotherapy
for Type 2 Diabetes.
Absorption Readily absorbed following
Drugs Similar to Glyburide (DiaBeta, Glynase)
PO administration
First-generation sulfonylureas are typically less potent,
Distribution Distributed widely to body require larger doses, have a shorter duration of action, and
require more frequent dosing than the second-generation
tissues, with greatest concen- sulfonylureas. Thus, the second-generation drugs are more
widely prescribed.
trations in liver, kidneys, and
First-generation sulfonylureas:
intestines; crosses the placenta Chlorpropamide (Diabinese): Approved in 1958, chlor-
propamide is the longest acting of the first-generation sul-
Primary metabolism Extensive hepatic metabolism fonylureas, with a duration of action of 24 to 72 hours. In
addition to treating type 2 diabetes, an unlabeled use is the
Primary excretion Equal in urine and feces treatment of neurogenic diabetes insipidus. Rarely, it can
produce an antidiuretic effect, with resulting hyponatre-
Onset of action 15–60 min mia, water intoxication, and edema. Due to the long half-
life of the drug (36 hours), hypoglycemia can be severe and
Duration of action Up to 24 h prolonged. It is a pregnancy category C drug.
Adverse Effects: The primary adverse effect of glyburide Tolazamide (Tolinase): Approved in 1965, tolazamide is
is hypoglycemia. Patients at increased risk for hypoglyce- structurally related to tolbutamide but is 5 times more
mia include those with CKD or hepatic insufficiency, those potent. It is taken once daily with breakfast. It can also be
consuming an improper diet, and patients who are older or used in patients who fail to respond to other sulfonylureas.
malnourished. Excessive exercise or alcohol consumption It is a pregnancy category C drug.
also increases the risk for hypoglycemia. Other adverse
effects of therapy include heartburn, nausea, vomiting, Tolbutamide (Orinase): Tolbutamide is a short-acting sulfo-
diarrhea, pruritus, erythema, urticaria, photosensitivity, nylurea, with a duration of 6 to 12 hours, given once or twice
and blurred vision. Rare, though serious, adverse effects daily after meals. Approved in 1957, it has been used in
include hepatotoxicity, cholestatic jaundice, aplastic anemia, patients being treated with insulin who have failed to respond
leukopenia, thrombocytopenia, and agranulocytosis. to other sulfonylureas. It is a pregnancy category C drug.
Contraindications/Precautions: Glyburide is con- Second-generation sulfonylureas:
traindicated in patients with a known sensitivity to sulfa Glimepiride (Amaryl): Approved in 1995, glimepiride
drugs or thiazide diuretics because sulfonylureas are can be used alone or in combination with insulin for
chemically similar to sulfa drugs. It is contraindicated as patients with type 2 diabetes. It is most often given
the primary treatment for type 1 diabetes, diabetic coma, once a day with the first meal of the day. More recently,
or DKA. The drug is used with caution in patients with glimepiride is included in a fixed-dose combination with
CKD or hepatic disease because the drug may accumulate pioglitazone (Duetact). Because of the increased risk for
to toxic levels. If used during pregnancy, glyburide should myocardial infarction (from rosiglitazone and piogli-
be discontinued at least 1 month before delivery because tazone), the fixed-dose combinations contain a black box
newborns exposed to sulfonylureas may develop severe
hypoglycemia lasting several days.
Drug Interactions: Using alcohol with glyburide can
cause hypoglycemia or hyperglycemia and has resulted
in a disulfiram-type response, with severe nausea,
vomiting, flushing, and palpitations. Drugs that can
increase hypoglycemia when taken with glyburide are oral
Chapter 66 Pharmacotherapy of Diabetes Mellitus 1217
warning regarding the increased risk for heart failure and insulin release, so it is able to lower glucose levels in
myocardial infarction. patients who no longer secrete insulin. In addition to low-
ering blood glucose levels, it lowers triglyceride levels,
Glipizide (Glucotrol): Approved in 1984, glipizide is lowers total and low-density lipoprotein (LDL) cholesterol
available in a standard tablet form and an extended release levels, and promotes weight loss.
(XL) tablet, which should not be crushed or chewed. In
addition to treating patients with type 2 diabetes who are Metformin is used off-label to treat women with poly-
unable to achieve glucose control with diet alone, it can be cystic ovary syndrome. Women with this syndrome have
used for short-term therapy for those who normally can insulin resistance and high serum insulin levels. Metformin
control their glucose levels by diet. Once-a-day dosing is reduces insulin resistance, which in turn lowers insulin and
given 30 minutes before the first meal of the day. androgen levels, thus restoring normal menstrual cycles
and ovulation.
CONNECTION Checkpoint 66.2
Mechanism of Action: Metformin reduces blood
Glyburide combined with alcohol can cause a disulfiram reaction. glucose levels by multiple mechanisms. The drug reduces
From what you learned in Chapter 27, what causes the symptoms gluconeogenesis, thereby suppressing hepatic production
of the disulfiram reaction and what are common symptoms of this of glucose. In addition, the drug decreases the intestinal
reaction? Answers to Connection Checkpoint questions are available reabsorption of glucose and increases the cellular uptake
on the faculty resources site. Please consult with your instructor. of glucose.
Biguanides Pharmacokinetics:
Metformin (Glucophage) is the only drug in this class. It is Route(s) PO (regular release tablets,
a preferred drug for managing type 2 diabetes because of
its effectiveness and safety. solution, and extended release
PROTOTYPE DRUG Metformin (Glucophage, preparations)
Glumetza, Others)
Absorption Approximately 50–60% of a dose
Classification Therapeutic: Antidiabetic drug
Pharmacologic: Biguanide reaches systemic circulation;
Therapeutic Effects and Uses: Approved in 1994, extended release forms are
metformin lowers blood glucose levels in patients with
type 2 diabetes who are unable to control glucose levels by absorbed very slowly
diet and exercise. It can be used alone or in combination
with sulfonylureas, alpha-glucosidase inhibitors, or insu- Distribution Distributed to most tissues;
lin. It is approved for use in children ages 10 and older.
Several formulations of metformin are available: crosses the placenta; secreted in
• Regular release tablets. Administered once or twice breast milk; not protein bound
daily, absorption is decreased with food, and the peak
plasma level is 2.5 hours. Primary metabolism Not metabolized
• Solution (Riomet). Administered once or twice daily, Primary excretion Kidneys
absorption is slightly increased with food, and the
peak plasma level is 2.3 hours. Onset of action Less than 1 h; peak action: 1–3 h
• Extended release (Fortamet, Glucophage XR, and Duration of action 12 h (regular release); 24 h
Glumetza). These are long-duration systems in which
metformin is slowly released from a semipermeable (extended release)
membrane (Fortamet), gel (Glucophage XR), or gastric-
retentive technology (Glumetza). Administered once Adverse Effects: The most common adverse effects
daily, absorption is significantly increased with food, that occur in 30% of patients taking metformin are GI
and the peak plasma level is 6 to 8 hours. related and include nausea, vomiting, abdominal dis-
comfort, metallic taste, diarrhea, anorexia, and moderate
Metformin reduces fasting and postprandial glucose weight loss. It may also cause headache, dizziness, agita-
levels. Because it does not promote insulin release, it does tion, and fatigue. Unlike the sulfonylureas, metformin
not cause hypoglycemia, which is a major advantage of the rarely causes hypoglycemia or weight gain. Black Box
drug. The drug actions do not depend on stimulating Warning: Lactic acidosis is a rare, though potentially fatal,
adverse effect of metformin therapy. The risk for lactic aci-
dosis is increased in patients with CKD or any condition
that puts them at risk for increased lactic acid production,
such as liver disease, severe infection, excessive alcohol
intake, shock, or hypoxemia.
Contraindications/Precautions: Metformin is con-
traindicated in patients with severe CKD, because the drug
can rise to toxic levels. It is also contraindicated in patients
with heart failure, liver failure, history of lactic acido-
sis, concurrent serious infection, or with any condition
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