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The contents of this blog contain topics relevant to end of life care written by our own hospice clinical pharmacists. Continue to check this site regularly for the newest post or subscribe to the RSS feed below.

Dr. Lori Osso-Connor has been working in the area of hospice and palliative care since 2002. She received both her bachelor degree and doctorate degree in pharmacy from Duquesne University in Pittsburgh, PA in 1995 and 2002 respectively. She received her board certification in geriatric pharmacy in 2014. Dr. Connor has been a clinical pharmacist in such practice setting as retail pharmacy, medication therapy management consultant, and hospice and palliative care consultant. She has been with Delta Care Rx since 2012 as a hospice clinical pharmacist.

Lori Osso-Connor, PharmD, CGP

Review of Addison’s Diease

Addison’s disease or adrenal insufficiency is a very rare hormonal disorder. It is so rare that this condition is often not discussed in end of life care. It can be useful to understand Addison’s disease and the management of this condition as many of these patients are on steroid therapy that may overlap with the hospice plan of care. This highlights importance of obtaining a complete and accurate medical history on admission to ensure that we have a full understanding of why the patient is on a current medication therapy.

Addison’s disease is a result of a hormanal change in the adrenal glands. The adrenal glands are walnut sized organs that sit on top of the kidneys. Their function is to produce cortisol, aldosterone, and DHEA (dehydroepiandrosterone) which are necessary for many functions in the body. There are two types of adrenal insufficiency: primary adrenal insufficiency and secondary adrenal insufficiency. Primary adrenal insufficiency occurs when the adrenals cannot produce enough cortisol and/or aldosterone due to some type of damage to the adrenals caused by an infection, virus, or autoimmunity. Approximately 80% of Addison’s disease is caused by an autoimmune disorder. This is when the body’s immune system attacks its own organs. Secondary adrenal insufficiency occurs when the pituitary in the brain fails to produce ACTH (adrenocortisotropin). Secondary adrenal insufficiency may be caused by the abrupt discontinuation of high doses of steroids, surgical removal of pituitary tumor, or a change in the pituitary gland function. ACTH is needed to stimulate the production of cortisol. If the ACTH is low, the cortisol will also be low.

The HPA axis (hypothalamic-pituitary-adrenal axis) is a negative feedback mechanism which functions to control cortisol levels. In the brain, the hypothalamus releases corticotrophin releasing hormone(CRH) which then signals the pituitary to release ACTH. ACTH signals the adrenals to make cortisol. When cortisol levels peak, there is a negative feedback that tells the hypothalamus to stop releasing CRH and thus the pituitary to stop making ACTH.

Cortisol, a glucocorticoid, aldosterone, a mineralcorticoid, and DHEA, sex hormones, have many functions in the human body. Cortisol helps to maintain blood pressure, regulate metabolism, and slows the inflammatory response. Aldosterone works to maintain blood pressure and balance sodium and potassium. If aldosterone is low, sodium is decreased and potassium is increased. DHEA makes the sex hormones androgen and estrogen.

The symptoms of adrenal insufficiency include: weight loss, fatigue, abdominal pain, muscle weakness, nausea and vomiting, hypotension, dizziness, hypoglycemia, and salt craving. Additionally, hyperpigmentation can occur in primary adrenal insufficiency. This is due to the high ACTH stimulation the melanocytes in the skin especially in the skin folds, elbows, knees, and palms of the hands.

The primary treatment for adrenal insufficiency is the replacement of oral hydrocortisone (a glucocorticoid) plus or minus fludrocortisone (a mineralcorticoid). If the patient becomes ill or has an accident and is unable to swallow, the injectable form of hydrocortisone must be administered. Events such as surgery or pregnancy would also cause those with adrenal insufficiency to be managed with the injectable formulation instead of oral. When a patient becomes ill, they must follow a stress dosing plan by doubling or tripling the steroid doses dependent on the numerical value of the fever as the body requires more cortisol to deal with the acute illness.

Patients must be very compliant or they could end up in an Addisonian crisis which could lead to shock and death. Symptoms of an adrenal crisis include: low blood pressure, low blood sodium, low blood glucose, and high blood potassium.

Adrenal insufficiency is diagnosed through blood and urine tests. This will help to determine the cortisol level. If the cortisol level is low, an ACTH stimulation test will be done. The patient will be given an IV injection of synthetic ACTH and samples of blood, urine or both are taken before and after the injection. If the cortisol rises in response to the ACTH, Addison’s can be ruled out. A little or no increase indicates adrenal insufficiency. If the ACTH test is abnormal, a CRH stimulation test can be done to determine the cause of the adrenal insufficiency. A patient is injected with synthetic CRH and blood is taken before, 30, 60, 90, 120 minutes after the injection. Addison’s patients will produce a high ACTH with no cortisol response. Those with secondary adrenal insufficiency will fail to produce ACTH or it is delayed. If it is delayed, the hypothalamus is the cause. If no ACTH is produced, the pituitary is the cause. Other tests may include an ultrasound of the abdomen to see if there are structural abnormalities in the adrenals, a tuberculin test, and antibody blood tests.

Those with adrenal insufficiency should always wear a medic alert bracelet to indicate that they are cortisol dependant. They also need to always carry the injectable form of the corticosteroid in the event of an emergency.

There is still a lot to learn with adrenal insufficiency. The recent article, The Diagnosis and Treatment of Primary Adrenal Insufficiency in the Journal of Clinical Endocrinology acknowledges that diagnostic procedures and treatment strategies are far from optimal. They also state that the validity of the adrenal function tests are questionable. Salivary cortisol testing which has been done by functional medicine for many years is only recently being acknowledged in the medical world as a biomarker. Liquid chromatography testing is also being studied as a diagnostic test. Additionally, replacing cortisol has no effect on the HPA axis and ACTH levels remain high. Drugs such as rituximab and tetracosactide has resulted in regeneration of cortisol production. Immunomodulatory treatment to stop the autoimmune response may eventually be the treatment for those with autoimmune adrenal insufficiency. They have also documented a successful adrenal transplantation. As you can see, much work needs done so that adrenal insufficiency can have a cure and not just a treatment.


References:
1. Bornstein, SR, Bruno A, Wiebke A, Andreas B, Don-Wauchope A, Hammer GD, et al. "Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline." The Journal of Clinical Endocrinology & Metabolism 101.2 (2016): 364-89. Web.
2. Loechner, K. "Adrenal Insufficiency and Addison's Disease." N.p., May 2014. Web. 12 Feb. 2016.

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Lori Osso-Connor, PharmD, CGP

Serotonin Syndrome in the Elderly

Serotonin Syndrome or serotonin toxicity occurs when there is overstimulation of the peripheral and central serotonin receptors which causes serotonin to accumulate in the body. Increased serotonin levels can occur through the following mechanisms: increased serotonin production, inhibition of serotonin reuptake, inhibition of serotonin metabolism, increased serotonin release, and/or stimulation of the serotonin receptor. Any medication or combination of medications that can increase the concentration of serotonin can cause serotonin syndrome. The medications most likely to be involved in contributing to serotonin syndrome include selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitor (SNRIs), tricyclic antidepressants (TCAs) or serotonin modulator antidepressants (trazodone).

SSRIs are often used in the treatment of depression. The elderly population is at increased risk of experiencing depression due to disability, co-morbid conditions, and/or the death of loved ones. Therefore, the use of antidepressants in the elderly is common. SSRIs exert their effect by blocking the reuptake of CNS neuron serotonin in the brain. Some examples of SSRIs include: Prozac (fluoxetine), Paxil (paroxetine), Celexa (citalopram), Lexapro (escitalopram), and Zoloft (sertraline).

Serotonin syndrome is often underdiagnosed and clinicians must be aware and identify early symptoms. Serotonin syndrome is diagnosed through clinical symptoms. The hallmark feature of serotonin syndrome is agitation. The common signs are usually a triad of features including: neuromuscular excitation (clonus, rigidity, hyperreflexia), autonomic stimulation (tachycardia, fever, sweating, diarrhea, hypertension), and changes in mental status (confusion, agitation, coma). The Hunter Serotonin Toxicity Criteria is recommended for diagnosing serotonin syndrome.

Serotonin syndrome may occur within minutes to hours of use of the offending medication(s). The severity could range from mild to severe, even resulting in death. Treatment consists of discontinuing the causative medication. Diazepam has been used to decrease hypertonicity. Serotonin antagonists such as cyproheptadine and chlorpromazine also have been used.
It is important for the pharmacist to be aware of medications that have the potential to cause serotonin syndrome and recognize to the signs and symptoms associated with it.

Medication Class Examples
Selective Serotonin Reuptake Inhibitors (SSRIs) citalopram (Celexa), fluoxetine (Prozac), fluvoxamine (Luvox), olanzapine/fluoxetine (Symbyax), paroxetine (Paxil)
Selective Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) duloxetine (Cymbalta), sibutramine (Meridia), venlafaxine (Effexor)
Triptans

almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), sumatriptan (Imitrex),

zolmitriptan (Zomig)

Miscellaneous

Medications- buspirone (Buspar), carbamazepine (Tegretol), cocaine, cyclobenzaprine (Flexeril), Fentanyl, 5-hydroxytryptophan, linezolid (Zyvox), lithium, L-tryptophan, meperidine (Demerol), methadone (Dolophine), methamphetamine (Desoxyn), methylene blue, metoclopramide (Reglan), mirtazapine (Remeron), ondansetron (Zofran), phenelzine (Nardil), selegiline (Eldepryl), St. John’s wart, tramadol (Ultram), tranylcypromine (Parnate), trazodone (Oleptro), valproic acid

Medication Classes- Ergot alkaloids, Tricyclic antidepressants

 


References:
1. Brown, Charles. "Drug-Induced Serotonin Syndrome." U.S. Pharmacist 17 Nov. 2010: Web. 27 Aug. 2015. 
2. Nguyen, Timothy, and Billy Sin. "A Case of an Older Adult Patients and Drugs Associated with Serotonin Syndrome." The Consultant Pharmacist 30.8 (2015): 455-57. 

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Lori Osso-Connor, PharmD, CGP

Role of Warfarin in Hospice and Palliative Care

Patients who make the hospice choice have opted for comfort measures and are no longer seeking life sustaining treatment. However, as hospice professionals encounter daily, many patients are admitted on medications that are considered treatment and are used for curative measures and not palliative measures.

The risk for thromboembolism in hospice and palliative care patients increases due to advanced age and diagnoses such as cancer or cardiomyopathy. Warfarin (Coumadin®) is indicated as treatment to prevent clotting in atrial fibrillation, thromboembolic disease, and artificial heart valves. It is a medication that poses a clinical challenge on whether to continue or discontinue when the patient becomes hospice appropriate. Warfarin’s mechanism of action is to inhibit Vitamin K epoxide reductase which decreases the Vitamin K in the body and decreases clotting. While warfarin is typically indicated as treatment, it could be argued that it is used in hospice and palliative care to provide comfort by reducing the risk of pain and swelling in the extremities due to DVT, unilateral weakness, or paralysis related to stroke.

However, there are several arguments that can be made to support the discontinuation of warfarin in hospice and palliative care. Some issues to consider include:

• The use of warfarin requires PT/INR lab work to ensure therapeutic efficacy. Studies have shown that hospice and palliative care patients require more frequent INR monitoring. These blood draws may be undesirable to the patient and or caregivers at this point in care. Additionally, poor venous access may make obtaining the blood difficult.

• Warfarin is a medication that has many drug-drug interactions including many antibiotics and drug-dietary interactions which could pose unnecessary complications to the patient. Some examples of drug–drug interactions with warfarin in which the anticoagulant effect is increased include levofloxacin (Levaquin ®), sulfamethoxazole/ trimethoprim (Bactrim ®), prednisone, and NSAIDS. In addition, Vitamin K rich foods may decrease the effects of warfarin. Therefore, it is most important to keep a consistent type diet.

• As intake declines or is erratic, the dietary vitamin K may fluctuate which could increase the risk of a bleed or clot.

• Nausea and vomiting could impact the medication adherence which may alter INR due to drug interactions.

• When a dose is changed, it takes 5-6 days to take full effect. If the PT/INR is not carefully managed, it leads to additional increases or decreases in the dose and a myriad of additional blood draws.

• The risk of an intracranial hemorrhage in a debilitated ambulatory patient who may fall is greater than the benefit in preventing a stroke.3

• The risk of a GI hemorrhage is about 8%.1

• The 1-year risk of stroke in atrial fibrillation is 2% in patients treated with warfarin and 4% in those untreated.1

Do the benefits of continuing outweigh the risks? Some factors to consider when facing this decision include: indication, prognosis, bleeding risk, thrombosis risk, nutritional status, appropriate monitoring, medication adherence, medication changes, and patient/family preferences. It is also important to consider whether a new clot will impair the patient’s function or quality of life. As one can see, the choice to discontinue warfarin is a difficult one and is not always clear cut. The risks verse the benefits in each patient must be assessed in accordance with the family and patient’s goals. This individualized approach will help the hospice care professional determine whether the benefits outweigh the risks to the patient and make an appropriate choice.


References:

1. Allen, Richard. “10 Drugs to Reconsider When a Patient Enrolls in Hospice.” NHPCO Newsline(2014): 5.

2. Hill, Robin, Kerri Martinez, Thomas Delate, and Daniel Witt. “A Descriptive Evaluation of Warfarin Use in Patients Receiving Hospice or Palliative Care Services.” Journal of Thrombosis and Thrombolysis 27.3 (2008): 334-39.

3. Von Gunten, Charles, David Weissman, and Janet Abraham. “Fast Fact #278 Warfarin and Palliative Care.” #278 Warfarin And Palliative Care. Web. 26 Feb. 2015

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