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ADDISON DISEASE
I May Look Great, But I Don’t Feel Well . . . . . . . . . . . Level II
Cynthia P. Koh-Knox, PharmD
CASE SUMMARY
A 19-year-old man presents to the emergency department after he is
found crying, confused, and disoriented by his mother. His mother
has noticed increasing fatigue, social withdrawal, and sleeping in
her son over the past 6 months. She has also noticed a darkening
of his skin even though he has spent less time outdoors. The patient
has a past medical history of hypothyroidism and type 1 diabetes
mellitus (DM). In the ER, hypotension, hyponatremia, low random
morning serum cortisol concentration, and elevated adrenocorticotropic hormone (ACTH) concentration confirm the diagnosis of
primary adrenal insufficiency, or Addison disease.
QUESTIONS
Problem Identification
1.a. Create a list of the patient’s drug therapy problems.
• Addison disease requiring pharmacologic replacement therapy.
• Uncontrolled hypothyroidism likely due to medication nonadherence as reported by the patient’s mother. Patient currently prescribed levothyroxine 100 mcg orally daily. Current
labs: TSH 25.8 mIU/L (normal 0.4–4.1 mIU/dL) and free
T4 0.41 ng/dL (normal 10–24.6 ng/dL).
• Uncontrolled type 1 DM, likely secondary to medication
nonadherence as reported by the patient’s mother. Patient currently prescribed Lantus 24 units subcutaneously at bedtime
and Novolog subcutaneously with meals using a 1:15 scale
carbohydrate counting ratio. Current labs: FBG 140 mg/dL
and A1C 8.7%.
1.b. What information (signs, symptoms, and laboratory values)
indicates the presence or severity of Addison disease?
• Symptoms: Weakness/fatigue, 2.5 kg weight loss/anorexia,
hyperpigmentation, nausea, low blood pressure, behavioral
changes.1–5
• Laboratory values: Hyponatremia, low-normal cortisol
serum concentration in AM, high normal ACTH serum
concentration.1–5
• Psychiatric symptoms: Lethargy, social withdrawal, sleeping
more, abhorrent activities, crying, confusion, and disorientation.
• Primary adrenal insufficiency (autoimmune polyglandular
syndrome APS) is seen in up to 2% of patients with type 1 DM.
APS is more common in patients who also have autoimmune
thyroiditis.3
Desired Outcome
2.What are the goals of pharmacotherapy in this case?
• The intended outcome for patients with Addison disease is
to establish cortisol and aldosterone replacement therapy to
• Educate the patient and his family to reinforce importance of
adherence because Addison disease, type 1 DM, and hypothyroidism require lifelong therapy.
• Prevent or minimize adverse effects of the medications, including episodes of hypoglycemia caused by insulin.
• Educate the patient about reporting signs and symptoms
associated with high or low cortisol or blood glucose serum
concentrations.
• Inform the patient about the risk of developing osteoporosis
due to chronic glucocorticoid therapy and recommend prevention strategies. (This may not be as significant of a concern to
this young man, as osteoporosis is often more concerning to
postmenopausal women.1)
• Educate patient on reducing daily stress and monitoring for
mood changes. During an Addisonian crisis, agitation, delirium, and hallucinations have been reported. These symptoms
might be the first presentation of a crisis in a patient who was
previously asymptomatic during therapy.2
Therapeutic Alternatives
3.a. What nondrug therapies might be useful for this patient?
• Nondrug therapies include stress management, proper diet
with appropriate sodium and glucose intake, exercise, and
regular monitoring of blood pressure and glucose serum concentrations. These strategies should be explained to the patient
so as to minimize or prevent undesirable side effects from
medications.
• Monitoring of daily sodium intake.6
• Avoidance of exposure to sunlight and extreme temperatures
to minimize sunburn and dehydration.
• Sick day rules education for patient and family members.5,6
• Patient and family education about preventing or recognizing
when an adrenal crisis or severe hypoglycemia or hyperglycemia may be occurring and what to do in these situations is
important.
• Patient and family education about the other conditions
associated with Addison disease therapy such as osteoporosis, weight gain, daytime fatigue, puffy/moon face, and
depression.1,5
• A medical alert bracelet or necklace stating “adrenal insufficiency” or “steroid-dependent” and “type 1 diabetes” is
advisable in case of an emergency. A medication or “steroid”
card listing current medications, physician name, and contact
information is also helpful.1,5
• A local or state support group may be helpful for patients and
families with Addison disease. There are many organizations
that provide information and support to families affected
by Addison disease, such as the National Adrenal Diseases
Foundation (www.nadf.us), Addison’s Disease Self-Help Group
(www.addisons.org.uk), and the National Endocrine and Metabolic Diseases Information Service (http://endocrine.niddk.nih
.gov/pubs/addison/addison.htm).
• Alternative therapies, such as massage, yoga, and meditation,
can be useful in dealing with fatigue, irritability, or tension
during the day.1
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Addison Disease
Zachary A. Weber, PharmD, BCPS, BCACP, CDE
• Eliminate symptoms and prevent acute adrenal crisis to
improve the patient’s quality of life.1
CHAPTER 89
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mimic normal circadian adrenal rhythm (refer to the textbook chapter on adrenal gland disorders for more detailed
information).
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SECTION 8
• Proper diet education is necessary to manage weight issues and
prevent dehydration.1
• Increased environmental temperature and humidity may
increase salt loss from sweating. Mineralocorticoid requirements may need to be monitored and adjusted.6
3.b.What feasible pharmacotherapeutic alternatives are available for the treatment of Addison disease?
Endocrinologic Disorders
• Cortisol replacement therapy with oral corticosteroids is necessary to replace that which is no longer being produced by the
adrenal glands. The available corticosteroids differ in duration
of action as well as in glucocorticoid, mineralocorticoid, and
sodium-retaining potencies. The cost of therapy for most products is low, and dosing regimens are simple. The lowest effective
dose should be used, and dosing schedules should mimic the
normal diurnal adrenal rhythm. There are no standard methods to assess adequate glucocorticoid replacement. The patient’s
well-being, tolerance of therapy, and development of symptoms
serve as good indicators of efficacy.1,6 Smaller, divided doses
three times daily may reduce symptoms of fatigue or irritability,
but adherence should be considered with this dosing schedule.1,6 Long-acting corticoids may be considered in patients
with type 1 DM to achieve tighter glycemic control.7
• As patient concerns are made known, they should be addressed
and referrals to support systems should be considered.
Optimal Plan
4.What drug, dosage form, dose, schedule, and duration of
therapy are best for this patient?
• Hydrocortisone 20 mg orally in the morning (9:00 AM) and
10 mg in the early evening (5:00 PM). (Patient received hydrocortisone 15 mg in the morning and 5 mg in the evening.)
✓Administration times for hydrocortisone may need to be
altered to resolve signs and symptoms reported by the
patient. Occasional symptoms of unusual thirst can be an
early sign of low hydrocortisone serum concentrations,
which might warrant an earlier administration of the second daily dose. Dosing can be changed to three times daily
(hydrocortisone 10 mg orally TID) if the patient can adhere
to an extra dose midday to attempt to minimize the daytime
fatigue. Do not administer corticosteroids prior to bedtime
to avoid sleep disruption.6 A small study of continuous subcutaneous hydrocortisone infusion demonstrated no added
benefits or improvement when compared to oral glucocorticoid therapy.9
✓Hydrocortisone, prednisone, and cortisone are the agents
of choice for cortisol replacement therapy. Usual morning
doses are hydrocortisone 20 mg, prednisone 5 mg, or cortisone 25 mg; evening doses of each agent given at 50% of
the morning dose will usually be adequate to duplicate the
normal circadian rhythm of cortisol production. In general,
the patient should try to take the second dose 6–8 hours
after the first dose.1,6
• Fludrocortisone 0.1 mg orally once daily in the morning.
✓Fludrocortisone acetate is a mineralocorticoid that may be
given to minimize development of hyperkalemia. It may
also help to control the symptoms of postural hypotension.
It may be added if the glucocorticoid used does not provide
sufficient mineralocorticoid potency, and a deficiency of
aldosterone is apparent by the continued presence of hyponatremia and hyperkalemia. The usual dose is 0.05–0.2 mg
orally once daily.1,6
• Continue levothyroxine 100 mcg daily (elevated TSH likely
secondary to medication nonadherence, not subtherapeutic
dosage).
✓Prednisolone, triamcinolone, methylprednisolone, betamethasone, and dexamethasone are alternative agents. However,
they offer no advantage over the previously listed options
and may be more expensive. Furthermore, use of any of
the latter four agents, which have little or no sodiumretaining potency, may make the addition of fludrocortisone
necessary.
• Oral dehydroepiandrosterone (DHEA) has been studied to
replace adrenal androgen serum concentrations in men and
women.1,8 DHEA has been studied to a greater extent in
women with primary adrenal insufficiency.8 Benefits may
include mood improvement, general well-being, osteoporosis
prevention, increased energy, less dry skin, and increased lean
muscle. Side effects reported include moderate weight gain,
oily skin, and acne.1,6
3.c.What psychosocial considerations are applicable to this
patient?
• Adrenal insufficiency therapy is a chronic condition, and the
ability to deal with the lifelong risk of developing adrenal
crisis must be present with strong family support. Quality
of life is impaired, and the predominant complaints are lack
of energy, fatigue, anxiety, depression, and decreased libido
(in women).1,2
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
✓If necessary, the fludrocortisone dose can be increased to a
maximum of 0.2 mg as necessary to control hyponatremia,
hyperkalemia, and orthostatic hypotension.
• Duration of therapy is lifelong, and individualized dosage
adjustments must be made according to the patient’s response
to therapy based on diminished clinical symptoms and normalization of serum laboratory tests.
✓ Increase Lantus to 26 units subcutaneously at bedtime, if it is
determined that the patient has been adherent to his current
regimen.
• It is important to approach adjustment of insulin cautiously,
as patients with Addison disease may be at increased risk of
hypoglycemia.10
✓Continue NovoLog 1:15 carbohydrate ratio, revise this dose
as needed when the patient provides documentation of his
self-monitored blood glucose values during his outpatient
follow-up. Can consider changing NovoLog to a set dose
with each meal, as this would provide a less complex regimen for the patient and may help improve adherence.
Outcome Evaluation
5.Which clinical and laboratory parameters are necessary to
evaluate the therapy for achievement of the desired therapeutic
outcome and to detect or prevent adverse effects?
• Although hyperpigmentation is not a universal marker in all
patients with Addison disease, a reduction in the patient’s pigmentation is a good clinical indicator of response to therapy.
• Confirm the patient’s adherence with therapy and assess his
overall sense of well-being.
• Monitor body weight, blood pressure, blood and urine glucose concentrations, ophthalmologic exams, and stool for
the presence of occult blood. The frequency of monitoring
these parameters varies depending on the resolution of signs
and symptoms. Body weight, blood pressure, and glucose
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• A majority of primary adrenal failure cases are a result
of organ-specific autoimmune disorders. Patients who are
affected by one endocrine disorder are at increased risk of
developing others. Examinations for gonadal failure, vitiligo,
celiac disease, myasthenia gravis, rheumatoid arthritis, and
pernicious anemia should be considered.1,3,5
• Monitor the patient’s hypothyroid condition after initiation
of cortisol and mineralocorticoid therapy. Check serum TSH
again in 6–8 weeks, and then at least every 12 months.
• Monitor A1C at least every 3 months to assess glycemic control.
• Routine bone mineral density monitoring is not required if
glucocorticoid replacement is adequate.6
• If you miss a morning dose and you remember in the morning,
take the missed dose. If you remember in the afternoon, skip
the morning dose and take the evening dose as scheduled.
• If you miss the evening dose and remember before going to
bed, take the missed dose. Otherwise, skip the dose and take
the next morning dose as scheduled. Never take double doses.
• Side effects of hydrocortisone include stomach irritation,
increased risk of infections, sodium retention and leg swelling
(edema), loss of body potassium and magnesium, cataracts,
delayed wound healing, and easy bruising. Your healthcare
providers will minimize these side effects by monitoring therapy and using the lowest dose and best dosing times necessary
to control your disease.
Fludrocortisone:
Patient Education
6.What information should be provided to the patient to
enhance adherence, ensure successful therapy, and minimize
adverse effects?
General information:
• The names of your medications are hydrocortisone, fludrocortisone, levothyroxine, Lantus, and NovoLog.
✓Hydrocortisone and fludrocortisone are intended to replace
the hormones normally produced by your adrenal gland.
You will need to take these medicines for the rest of your life.
✓Levothyroxine is meant to replace one of the hormones normally produced by the thyroid gland. You will likely need to
take this medicine for the rest of your life.
✓Lantus and NovoLog insulin are meant to replace insulin
that is normally secreted by the pancreas. You will need to
take these medicines for the rest of your life.
• Stressful situations, such as surgery, infection, or trauma, can
trigger what is called an “adrenal crisis.” This means that your
body is not producing or receiving the amount of steroid
hormones needed to endure the stress and maintain normal
body functions. Signs and symptoms of adrenal crisis include
headache, nausea, vomiting, dizziness, extreme weakness, or
severe drop in blood pressure. If you experience any of these
symptoms, seek immediate medical attention. Do not hesitate
to call 911.
• It is important to wear or carry identification stating that you
are taking chronic corticosteroid and insulin therapy in case of
a serious illness or other emergency situation.
• Always ask your physician or pharmacist about new medications that are prescribed or over-the-counter drugs you may
wish to use to ensure that they are compatible with these
medications.
Hydrocortisone:
• You will be taking a larger dose of this medication in the morning with breakfast and a smaller dose in the evening. This is
intended to mimic the way your body normally produces the
natural steroid hormone. Try to take the two doses approximately 6–8 hours apart. You might try to take the second dose
of your hydrocortisone close to dinner time. This may help
with the daytime fatigue. In addition, taking this medication
with food will help minimize stomach upset.
• This medication helps to normalize the amount of sodium and
potassium in your body and also helps to control your symptoms of dizziness when you stand.
• Take this medicine just once daily. Choose a time that is convenient for you such as in the morning, and maintain consistency with the time. You may take it at the same time as the
hydrocortisone.
• Side effects are minimal but may include upset stomach, leg
swelling, and low blood potassium concentrations. Taking this
medication with food will help minimize stomach upset.
• If you feel thirsty and urinate frequently, it is important
to be tested for kidney problems and to have your level of
diabetes control evaluated. If those conditions are ruled
out, the symptoms may be associated with the timing of the
fludrocortisone.
Levothyroxine:
• Take on an empty stomach first thing each morning.
• Side effects if your dose is too high may include: increased
heart rate, warm feeling, fast breathing, low blood sugar, weight
loss, or a general feeling of your metabolism speeding up.
• Side effects if your dose is too low may include fatigue, weight
gain, cold feeling, shortness of breath, low heart rate, or a general feeling of your metabolism slowing down.
Lantus:
• Take this insulin every day, even if you are sick and/or not
eating.
• Take this insulin at the same time every day (it does not necessarily have to be at bedtime; choose a convenient time that you
will remember every day).
• The main side effects are low blood sugar (symptoms include
confusion, dizziness, shakiness, sweating, irritability, fast heartbeat, headache, and fatigue) and weight gain.
NovoLog:
• This insulin should be taken 15 minutes before to 15 minutes
after each meal.
• If you skip a meal, skip a dose of this insulin.
• The main side effects are low blood sugar (symptoms include
confusion, dizziness, shakiness, sweating, irritability, fast heartbeat, headache, and fatigue) and weight gain.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Addison Disease
• Clinicians may opt to perform annual adrenal function studies
such as the ACTH stimulation test.1,5
• Never stop taking this medication or change your dose unless
your physician instructs you to do so. This medication requires
gradual tapering if you need to stop therapy.
CHAPTER 89
monitoring are relatively easy for self-monitoring and less
costly than the other parameters.
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Symptoms that may require dose adjustments:
SECTION 8
• Symptoms associated with low or high serum cortisol concentrations can usually be treated with dose adjustments. It is
important to inform your doctor of these symptoms in case
further testing is needed to identify other possible causes.
• Symptoms of low serum cortisol concentrations1:
✓Exhaustion (“hitting the wall”), nausea, loss of appetite, and
vomiting are common symptoms.
Endocrinologic Disorders
✓Feeling “lousy” at certain times of day may occur.
✓Hydrocortisone can cause protein loss in the skin structure
resulting in thinning skin. Dose adjustments can resolve this
problem.
✓Muscle weakness and decreased muscle strength may be a
sign of potassium imbalance.
✓“Moon face” or puffiness is common due to high doses or
long-term use of steroids. Reduction in doses needs to be
evaluated by the physician to weigh the benefits against the
risks.
✓Dry and cracking skin is common and can be treated with
emollient creams.
✓Low blood glucose or “brain fog” may present as feelings
of unsteadiness, irritability, lightheadedness, and hunger.
Cycles of low energy can be caused by your body’s ability
to produce too much insulin in response to high sugar and
high fat foods. Avoid eating these types of foods to “gain”
energy. Protein-rich foods are the best way to combat low
blood sugar.
✓Joint aches and recurrent headaches can occur.
✓ Feeling thirsty and frequent urination may indicate a need to
increase your fludrocortisone medication.
✓ Salt, acid, or sugar cravings are common. Tell your physician
what time of day these cravings occur, as they may be related
to the timing of your divided doses.
✓If your skin pigmentation does not fade, this could indicate
that your medication doses may need to be adjusted. Pigmentation should fade within weeks of initiating medication.
• Symptoms of high cortisol serum concentrations1:
✓Sleeping difficulties are common.
✓Mood swings, anger, and depression are common but need
to be interpreted with caution before starting antidepressants or mood enhancers.
✓Fluid retention should be carefully assessed to determine if
it is related to high serum fludrocortisone concentrations
or a variety of other conditions such as hypothyroidism or
kidney problems.
✓Hydrocortisone can make capillaries fragile, leading to easy
bruising. If the hydrocortisone dose is correct, easy bruising
should be minimal or nonexistent.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
REFERENCES
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http://www.addisons.org.uk/info/manual/adshgguidelines.pdf. Accessed
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3508960/. Accessed
December 2, 2015.
3. Kordonouri O, Maguire AM, Knip M, et al. Other complications and
associated conditions with diabetes in children and adolescents. Ped
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principles. Amer Fam Phys 2014;89(7):563–568.
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6. Reisch N, Arlt W. Fine tuning for quality of life: 21st century approach
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7. Petersen KS, Rushworth RL, Clifton PM, et al. Recurrent nocturnal
hypoglycaemia as a cause for morning fatigue in treated Addison’s
disease—a favourable response to dietary management: a case report.
BMC Endocrine Disorders 2015;15:61.
8. Arlt W. The approach to the adult with newly diagnosed adrenal insufficiency. J Clin Endocrinol Metab 2009;94(4):1059–1067.
9. Gagliardi L, Nenke AM, Tilenka RJ, et al. Continuous subcutaneous hydrocortisone infusion therapy in Addison’s disease: a randomized, placebo-controlled clinical trial. J Clin Endocrinol Metab
2014;99:4149–4157.
10. Elbelt U, Hahner S, Allolio B. Altered insulin requirement in patient
with type 1 diabetes and primary adrenal insufficiency receiving standard glucocorticoid replacement therapy. Eur J Endocrin
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