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Pharmacy Review Module 07: Pharmacotherapy for Endocrine and Exocrine Disorders
Accreditation Information
ASCP is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
This home study web activity has been assigned 5 credit hours. ACPE UPN: 0203-0000-10-040-H01-P Release Date: 4/1/2010 Expiration Date: 4/1/2013
To receive continuing education credit for this course, participants must complete an on-line evaluation form and pass the online assessment with a score of 70% or better. If you do not receive a minimum score of 70% or better on the assessment, you are permitted 4 retakes. After passing the assessment, you can print and track your continuing education statements of credit online.
Geriatric Pharmacy Review courses have not yet been approved for Florida consultant pharmacy continuing education.
Content Experts
Mary Caputi, PharmD, CDE, BC-ADM, CGP Department of Veterans Affairs Hickory Outpatient Clinic Dennis J. Chapron, MS, RPh Medication Safety Officer Saint Francis Hospital and Medical Center Sean M. Jeffery, PharmD, CGP, FASCP Associate Clinical Professor University of Connecticut School of Pharmacy & Clinical Pharmacy Specialist Geriatrics and Extended Care Connecticut VA Healthcare System Jennifer M. Voisine, PharmD, BCPS Geriatrics Pharmacy Resident Connecticut VA Healthcare System & Adjunct Assistant Professor University of Connecticut School of Pharmacy
Marie Parker, PharmD, BCPS Clinical Pharmacist Humana Pharmacy Solutions Jennifer J. Lee, PharmD, BCPS, CDE Assistant Clinical Professor University of Connecticut School of Pharmacy & Clinical Pharmacist in Ambulatory Care/Womens Health Connecticut Healthcare System
Legacy Expert: Stephen M. Setter, PharmD, CDE, CGP, DVM College of Pharmacy Department of Pharmacotherapy Washington State University
Mary Caputi has no relevant financial relationships to disclose. Dennis J. Chapron has no relevant financial relationships to disclose. Sean M. Jeffery has no relevant financial relationships to disclose. Jennifer J. Lee has no relevant financial relationships to disclose. Jennifer M. Voisine has no relevant financial relationships to disclose. Marie Parker has no relevant financial relationships to disclose. Stephen Setter has no relevant financial relationships to disclose.
Learning Objectives
By the end of this Review Concept you should be able to: Compare and contrast the epidemiology, pathology, and clinical presentation of diabetes mellitus type 2 in the younger versus older individual. Describe microvascular, macrovascular, and other complications which can occur in a patient with diabetes and how they may present differently in the older patient.
www.cdc.gov/diabetes/statistics/incidence/fig1.htm
http://www.cdc.gov/diabetes/statistics/age/fig1.htm Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, 2007. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2008. Copyright 2011 American Society of Consultant Pharmacists
http://www.cdc.gov/diabetes/statistics/duration/fig4.htm.
The incidence and prevalence of type 2 diabetes continues to increase throughout the world. Coincident with the aging of the population and the increase in obesity, the incidence of Diabetes will likely increase in those >65 years of age. This trend has already been documented. There are two types of diabetes; type 1 and type 2. Type 1 diabetes is associated with beta cell destruction because of either an autoimmune or idiopathic process which eventually leads to absolute insulin deficiency. This can occur at any age including the older patient. Type 1 accounts for approximately 5% of diabetes cases. In comparison, type 2 diabetes accounts for approximately 90 to 95 percent of reported cases. Type 2 diabetes is characterized by a combination of insulin resistance and beta-cell secretory defects. Progressive beta-cell dysfunction can lead to absolute insulin deficiency. Type 2 diabetes historically occurred more frequently in adults but recent statistics report increased frequency in adolescents and young adults. Management of type 1 diabetes requires exogenous insulin while type 2 diabetes management includes lifestyle changes [diet, exercise], oral medications and injectable products such as insulin, exenatide and pramlintide. Complications of type 1 and type 2 diabetes can be life-threatening, occur in multiple organ systems, and result in loss of quality and quantity of life. Management of complications results in significant healthcare burden. Total cost of care will increase as the population ages, diabetes occurs more frequently in the younger population, and the duration of diabetes increases. Prevention of diabetes, early detection and aggressive management of diabetes are key components to reducing complications and health costs.
Pre-Diabetes
Recently the American Diabetes Association added a new category to the classification of diabetes. Glucose abnormalities include impaired fasting glucose [IFG] and impaired glucose tolerance [IGT]. Individuals with IFG and IGT are considered to have Pre-diabetes and are at greater risk of progressing to diabetes and developing heart disease and stroke Pre-diabetes Population Trends In 19881994, among U.S. adults aged 4074 years, 33.8% had IFG, 15.4% had IGT, and 40.1% had prediabetes (IGT or IFG or both). In 20032006, 25.9% of U.S. adults aged 20 years or older had IFG (35.4% of adults aged 60 years or older). Applying this percentage to the entire U.S. population in 2007 yields an estimated 57 million American adults aged 20 years or older with IFG, suggesting that at least 57 million American adults had prediabetes in 2007. After adjusting for population age and sex differences, IFG prevalence among U.S. adults aged 20 years or older in 20032006 was 21.1% for non-Hispanic blacks, 25.1% for non-Hispanic whites, and 26.1% for Mexican Americans.
Pre-Diabetes
People with pre-diabetes can have impaired fasting glucose or IFG, impaired glucose tolerance or IGT or both IFG and IGT. The classification of pre-diabetes is based on a fasting glucose result and the results of a 2-hour glucose tolerance test. In those with IFG the fasting blood sugar level is 100 to 125 milligrams per deciliter (mg/dL) after an overnight fast. This level is higher than normal but not high enough to be classified as diabetes. In those with IGT the blood sugar level is 140 to 199 mg/dL after a 2-hour oral glucose tolerance test. This level is higher than normal but not high enough to be classified as diabetes. Management of those with pre-diabetes includes lifestyle changes, emphasizing dietary modification and increasing activity levels. Medication such as metformin can be added to management but dietary and activity changes provide the greatest benefits.
It is estimated that 18.2 million Americans have the endocrine disorder known as diabetes mellitus. Of the six hundred twenty-five thousand new cases per year, about fifty percent of them occur in individuals over fifty-five years of age. There are two primary or main types of diabetes mellitus that differ in terms of when they are diagnosed and how they are controlled and managed. Five to ten percent of diabetes patients have Type 1, and are dependent on exogenous insulin for survival. This type of diabetes is generally diagnosed before age thirty. The other ninety to ninety-five percent of patients with diabetes have Type 2, which may be controlled with diet (medical nutrition therapy), exercise (physical activity), oral agents and/or insulin.
http://www.diabetes.org/diabetes-statistics/complications.jsp
Diabetes mellitus is characterized by changes in the metabolism of carbohydrate, protein and fat. To understand these changes , it is important to understand normal regulation of blood glucose. After food intake, metabolism of carbohydrate and protein results in increased blood glucose, and in turn, increased insulin secretion from the beta cells. Increased insulin levels facilitate glucose transport into peripheral cells. Blood glucose is also stored in the liver as glycogen through glycogenesis. Glycogenolysis, the breakdown of glycogen to glucose, is inhibited. These processes maintain normal blood glucose. In the fasting state, plasma glucose levels are maintained by regulation of hepatic glucose production and peripheral glucose utilization. When serum insulin levels fall, glucagon stimulates hepatic glucose production [through glycogenolysis and gluconeogenesis] to raise blood glucose levels. If glucose is unavailable, fats are converted to free fatty acids and ultimately keto acids.
Fasting hyperglycemia is diagnostic for type 2 diabetes and is evidence of beta-cell loss/failure. Fasting plasma insulin levels are elevated as a result of insulin resistance and up-regulation of beta-cells in an attempt to overcome it. Early in diabetes this can compensate for the hyperglycemia but, eventually, insulin production is insufficient to maintain normal glucose levels. As fasting blood glucose levels rise the rapid first phase insulin response to oral glucose is lost but late phase insulin release is normal or increased. As the level of glycemia increases further, insulin secretion is impaired [beta-cell dysfunction] and hepatic glucose production [glycogenolysis/gluconeogenesis] becomes prominent. Insulin resistance is seen in muscle and adipose tissues. Post-prandial hyperglycemia stimulates insulin secretion in an attempt to normalize plasma glucose. Insulin receptor and post-receptor binding defects result in further increases in insulin levels. Beta-cell dysfunction reduces insulin secretion and hyperglycemia worsens. Lipolysis becomes an energy source when glucose transport into cells is reduced. Free-fatty acid production further impairs insulin sensitivity and hyperglycemia worsens.
Insulin resistance is a central component of the metabolic syndrome and it significantly increases the risk of cardiovascular morbidity and mortality. Insulin resistance is present when large amounts of insulin (endogenous or exogenous) are required for a normal biologic response. The insulin resistance that triggers this series of events can be due to tissue and cellular defects. Obesity is often seen in type 2 diabetes and may directly contribute to insulin resistance. Adipose cells can be considered an endocrine organ because it influences insulin action through release of free fatty acids and secretion of proinflammatory mediators such as Tumor Necrosis Factor-alpha, and Interleukin-6. It also modulates hormones such as adiponection, leptin, and resistin. Research is ongoing on the impact of these hormones and their role in the development of diabetes. Target cell defects, such as the mutation of the insulinreceptor gene, problems with intracellular glucose transporters and cellular inhibitors worsen the relative glucose deficiency. In the older adult, stress and hormone disorders can also affect target cells and contribute to insulin resistance. Hormones implicated include corticosteroids, growth hormone, catecholamines, glucagon and thyroid hormone.
Copyright 2011 American Society of Consultant Pharmacists
Cadiovascular disease [CVD] is a major cause of morbidity and mortality in patients with Diabetes. Hypertension and dyslipidemia are often present in patients with diabetes and confer additional risk beyond that of diabetes. Aggressive lifestyle change and medication for blood pressure and cholesterol are required to reduce cardiovascular and cerebrovascular risk. Peripheral vascular disease, neuropathy and impaired circulation increase risk of foot infections and limb amputations. These contribute to morbidity, disability, and reduced quality of life in people with diabetes. As reviewed previously, diabetes is the leading cause of limb amputations and End Stage Renal Disease requiring dialysis. Early recognition and management of risk factors can prevent or delay complications..
More Information Additional information regarding testing, diagnosis and management of macrovascular complications review the Standards of Medical Care in Diabetes 2009 [Reference below].
While the macrovascular complications of diabetes are the ones most likely to result in death, it is the microvascular complications that result in the greatest impact on the persons quality of life and degree of disability. Up to 70% of people with diabetes will experience nervous system damage in their lifetime. The pain and discomfort caused by diabetic neuropathy, at a minimum, contributes to a diminished quality of life. At its worst, diabetic neuropathy is a major contributing cause of lower-limb amputation. Macrovascular Complications: Retinopathy Nephropathy Neuropathy Retinopathy Diabetic retinopathy is the leading cause of legal blindness in people with Diabetes in the United States. Retinopathy occurs as a result of elevated glucose levels which cause structural, physiological and biochemical changes that alter cellular metabolism, retina blood flow and retinal capillary function. The first manifestation of diabetic retinopathy is abnormalities in the retinal blood vessels such as microaneurysms. If these are detected, more are likely to occur. If these are not addressed, diabetic retinopathy can progress from a mild, asymptomatic form to severe, rapidly progressing retinopathy. In addition to diabetic retinopathy, cataracts and glaucoma are also leading causes of blindness. The development and progression of diabetic retinopathy correlate strongly with glycemic control and duration of diabetes. Modifiable risk factors for retinopathy include hyperglycemia and blood pressure. Intensive management of both are important in slowing the progression of retinopathy.
Copyright 2011 American Society of Consultant Pharmacists
Nephropathy Diabetic nephropathy is defined by macroalbuminuria: urinary albumin excretion of more than 300 milligrams in a 24-hour collection or macroalbuminuria and abnormal renal function characterized by abnormal serum creatinine, calculated creatinine clearance, or glomerular filtration rate (GFR). Diabetic nephropathy if the most common cause of end-stage kidney disease in the United states. Approximately onequarter to one-third of patients with type 1 or type 2 diabetes develop this to some degree. The American Diabetes Association recommends the random spot urine collection for nephropathy screening. All patients with Diabetes should be tested annually for the presence of microalbuminuria [trace levels of albumin in the urine, an indicator of early nephropathy].
Copyright 2011 American Society of Consultant Pharmacists
Paresthesias, impaired sensation or pain in the feet or hands known or abnormal sensations such as burning, tingling, pricking Gastroparesis, slowed digestion of food in the stomach Carpal tunnel syndrome Muscle weakness Impotence Postural hypotension Diarrhea The microvascular complications of diabetes arise from long term complications of diabetes affecting small blood vessels. These classically have included retinopathy, nephropathy and neuropathy. Retinopathy is divided into two main categories. Non-proliferative retinopathy and proliferative retinopathy. Non-proliferative retinopathy can be recognized by development of microaneurysms, venous loops, retinal hemorrhages, hard exudates and soft exudates. Proliferative retinopathy is defined as presence of new blood vessels with or without vitreous hemorrhage. Proliferative retinopathy represents a progression of non-proliferative retinopathy. Diabetic nephropathy is defined as the presence of persistent proteinuria >0.5 gms/24 hours. Overt nephropathy is characterized by progressive decline in renal function resulting in end stage renal disease. Neuropathy is a heterogenious condition that is associated with nerve pathology. The condition is classified according to the nerves affected. The classification of neuropathy includes focal, diffuse, sensory, motor and autonomic neuropathy.
Copyright 2011 American Society of Consultant Pharmacists
Life-threatening complications of diabetes include DKA (diabetic kito acidous) and HHNS (hypersmolar hyperglycemic non-ketotic syndrome). Insulin deficiency, either relative or absolute, and elevated levels of stress-responding, hormones (e.g., glucagon, catecholamines, growth hormone, and cortisol) are involved in the development of these conditions. These complications can be seen in type 1 or type 2 diabetes. DKA is usually seen in patients with type 1 diabetes and HHNS in patients with type 2 disease. The clinical management of these syndromes involves careful evaluation and correction of the metabolic and volume status of the patient, identification and treatment of precipitating and comorbid conditions, implementation of a treatment regimen and a plan to prevent recurrence.
Asymptomatic patients and those at high-risk of developing diabetes should be screened according to the 2009 ADA Standards. Testing should be considered in all adults who are overweight (Body Mass Index greater than 25 kilograms per meter squared) and have additional risk factors such as physical inactivity and family history. In the absence of any specific risk factors, testing for pre-diabetes and diabetes should begin at the age of 45 years. If results are normal, testing should be repeated at 3-year intervals, with more frequent testing depending on initial results and risk status.
Another recent change is the American Diabetes Association recommendation to use the estimated average glucose, or eAG when reporting the A1C to patients.
A calculator for converting A1C results into eAG, in either mg/dl or mmol/l,and other professional and patient information materials are available at http://professional.diabetes.org/eAG
Retreived from http://care.diabetesjournals.org/content/32/Supplement_1/S13.full.pdf+html
There are many factors which contribute to the development of diabetes in the elderly. These include physiologic changes associated with the normal aging process such as reduced beta-cell volume and function, insulin resistance, and hypertension. Lifestyle risk factors include obesity, diet, and decreased physical activity or mobility concerns. Multiple comorbid illnesses and the pharmacotherapy for these conditions may precipitate hyperglycemia and increase the risk of diabetes. For example, persons who require corticosteroid treatment to control diseases such as Rheumatoid Arthritis, Chronic Obstructive Lung Disease or other acute conditions treated with intermittent steroid use may be prone to hyperglycemia. Nutrition, activity level, and obesity are modifiable risk factors in comparison to age and beta-cell loss. It is important to provide education on lifestyle changes which reduce the risk of developing diabetes. A modest weight loss of 5-7% of body weight can reduce the risk of diabetes and improve blood pressure and cholesterol. In patients with diabetes, the same weight loss can reduce insulin resistance and improve glycemic control. Older persons should be encouraged to start an activity program such as walking if medically approved.
Resources
For additional information, see: American Diabetes Association. Position Statement. Standards of Medical Care in Diabetes. Diabetes Care 32:S13S61, 2009 by the American Diabetes Association American Association of Diabetes Educators: Position Statement: Special considerations for the education and management of older adults with diabetes. The Diabetes Educator 2002;26:37-39. The Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med, 2002 346 6:393-403. The Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001 344[18]: 1343-1350. Gallagher EJ, LeRoith d, Karnieli E. The Metabolic Syndrome-from Insulin Resistance to Obesity and Diabetes. Endocrinol Metabol Clin N Am 2008 37;559-579. Gregg EW, Gu Q,Cheng YJ, Narayan, KM, Cowie CC. Mortality Trends in Men and Women with Diabetes, 1971 to 2000. Ann Intern Med. 2007 June 18 147:149-155. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil AW. 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N Engl J Med 2008;359:1577-89. The International Expert Committee. International Expert Committee Report on the Role of the A1C Assay in the Diagnosis of Diabetes. Diabetes Care July 2009 32:1327-1334.
Resources
Liebovitz, HE; editor. Therapy for Diabetes Mellitus and Related Disorders. 4th ed. Alexandria [VA]: American Diabetes Association; 2004. Meneilly GS. Diabetes in the elderly. Med Clin N Am 2006 90:909-923. Mensing C. editor in chief, Cypress M, Halstenson C, McLaughlin s, Walker EA, section editors. The Art and Science of Diabetes Self-Management Education, A Desk Reference for Healthcare Professionals.Chicago, American Association of diabetes Educators; 2006. Pan X-R, Li G-W, Wang J-X, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and Diabetes Study. Diabetes Care 1997;20:537-44. Tuomilehto J, Lindstrm J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343-50.
Resources
The American Diabetes Association: http://www.diabetes.org The American Association of Clinical Endocrinologists http://www.aace.com. American Association of Diabetes Educators, http://www.diabeteseducator.org The American Geriatrics Society: Guidelines for Improving the Care of the Older Person with Diabetes Mellitus . California Healthcare Foundation/American Geriatrics Society Panel on Improving Care for Elders with Diabetes [JAGS 51:S265S280, 2003 2003 by the American Geriatrics Society]. URL: http://www.americangeriatrics.org/products/positionpapers/JAGSfinal05.pdf The Centers for Disease Control and Prevention. http://www.cdc.gov/diabetes/index.htm The National Diabetes Education Program : http://ndep.nih.gov/ The National Institute for Diabetes & Digestive & Kidney Disease; http://www2.niddk.nih.gov/
By the end of this Review you should be able to: Classify an older adult as having diabetes mellitus given clinical presentation and laboratory data. Construct a treatment plan for an elderly individual given a patient case, taking into account patient and age-related variables. Educate an elderly individual on the non-pharmacologic and pharmacologic management of their diabetes.
The American Diabetes Association recommendations for glycemic control can be found above. These goals may be appropriate for some elderly individuals but, frequently, treatment goals must be adjusted to facilitate improved control with less risk of hypoglycemia.
Management of hyperglycemia in type 2 diabetes - Summary of An1diabe1c Interven1ons Interven1on Step 1: IniGal Lifestyle changes to decrease weight and increase acGvity Expected Decrease in A1C [%] 1-2 Advantages - Disadvantages Advantages: -Low cost, benets beyond weight loss Disadvantages: -IntervenGons fail for most paGents within the rst year 1.5 Advantages: -Weight neutral - Inexpensive Disadvantages: - ProblemaGc GastrointesGnal side eects - Rare lacGc acidosis - LimitaGons based on serum creaGnine
MeGormin
Management of hyperglycemia in type 2 diabetes - Summary of An1diabe1c Interven1ons Interven1on Step 2: Addi1onal Therapy Insulin 1.5-2.5 Advantages: - No dose limitaGon - Inexpensive [depends on product selecGon] -Improvements in Lipid Prole Disadvantages: - InjecGons - Frequent monitoring - PotenGal for hypoglycemia - Weight gain - Frequent glucose tesGng Sulfonylureas 1.5 Advantages: - Inexpensive Disadvantages: - Weight gain - Hypoglycemia [relaGvely infrequent]* Expected Decrease in A1C [%] Advantages - Disadvantages
Management
of
hyperglycemia
in
type
2
diabetes
-
Summary
of
An1diabe1c
Interven1ons
Interven1on
Thiazolidinediones
Expected
Decrease
in
A1C
[%]
0.51.4
Advantages
-
Disadvantages
Advantages:
-Improvements
in
Lipid
Prole
Disadvantages:
-Fluid
retenGon
-Weight
gain
-High
cost
-LimitaGons
due
to
co-morbid
diagnoses
such
as
Heart
Failure
Alpha-glucosidase
Inhibitors
0.5
0.8
Advantages:
-Weight
neutral
Disadvantages:
-GastrointesGnal
side
eects
[atulence]
-Three
Gmes
a
day
dosing
-High
cost
Megli1nides**
1-1.5
Advantages:
-short
duraGon
of
acGon
Disadvantages:
-Three
Gmes
a
day
dosing
before
meals
-High
cost
Copyright 2011 American Society of Consultant Pharmacists
Management of hyperglycemia in type 2 diabetes - Summary of An1diabe1c Interven1ons Interven1on DPP-IV Inhibitors Expected Decrease in A1C [%] 0.48-0.85 Advantages - Disadvantages Advantages: -Once daily dosing -Minimal risk of hypoglycemia as monotherapy -Improvements in fasGng and post-prandial glucose levels -Lack of weight gain -RelaGvely mild side-eect prole Disadvantages: -Cost -CauGon when used in renal dysfuncGon Exena1de 0.5 1.0 Advantages: -Weight loss Disadvantages: -InjecGons -Frequent gastrointesGnal side eects -High cost -Scant long-term use data
Management
of
hyperglycemia
in
type
2
diabetes
-
Summary
of
An1diabe1c
Interven1ons
Interven1on
Pramlin1de
Expected
Decrease
in
A1C
[%]
0.5-1.0
Advantages
-
Disadvantages
Advantages:
-Weight
loss
Disadvantages:
-MulGple
daily
injecGons
[pre-meal]
-GastrointesGnal
side
eects
-High
cost
-Scant
long-term
data
*Severe hypoglycemia is relatively infrequent with sulfonylurea therapy. The longer-acting agents (e.g. chlorpropamide, glyburide, and sustained release glipizide) are more likely to cause hypoglycemia than glipizide, glimepiride .**Repaglinide is more effective at lowering A1C than nateglinide
Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy. Diabetes Care 31: 174, 2008 by the American Diabetes Association, Inc., and Springer.
First generation sulfonylureas are rarely used in the elderly because of the long duration of action, hypoglycemia risk, and the availability of safer medications.
Oral sulfonylureas are a cost-effective choice for controlling hyperglycemia. They are indicated for use in type 2 diabetes when hyperglycemia is not controlled after an adequate trial of diet and exercise. They can be used as monotherapy or in combination with other oral agents. All sulfonylureas stimulate the release of insulin from pancreatic beta cells and enhance beta cell sensitivity to glucose. Because these agents increase insulin release, they are also known as secretagogues. The side effect and drug interaction profile of the second generation agents is similar to that of the first generation products. Hypoglycemia is the side effect of main concern for both types. This can be prolonged and more severe than insulin-induced hypoglycemia because of the longer half-life and duration of action of the sulfonylureas. Renal function and pharmacokinetic parameters must be considered when selecting a sulfonylurea for use in an elderly individual.
Meglitinides
Repaglinide [Prandin] Indications Adjunct to nutrition and exercise to lower blood glucose in patients with type 2 diabetes who have not met goals through lifestyle changes Use in combination with metformin or thiazolidinedione Contraindications/Precautions Patients with ketoacidosis and/or type 1 diabetes Increased risk of hypoglycemia in the elderly or those with renal or hepatic impairment Secondary failure may occur over time Not indicated for use with NPH insulin Mechanism of Action Meglitinides are structurally unrelated to sulfonulyreas but they lower glucose levels by stimulating insulin release from the pancreas. Insulin release is dependent on functioning beta-cells and is also dependent on glucose levels. Insulin release decreases at lower glucose concentrations. Peak action: 1 hour Duration of action; half-life: 1 hour Metabolites: inactive Excretion: urine 0.1% excreted unchanged; feces 90%
Meglitinides
Dosing: Administer at the start of the meal or within 15-30 minutes before the meal If an extra meal is eaten or a meal is skipped, a dose should be added or omitted. If A1C <8% and treatment naive: 0.5 mg initial dose before the meal If A1C >8% previously treated: initial dose 1-2 mg before each meal Dose adjustments are guided by glucose response and can be increased until goal glycemic control is achieved Adjustments should be done at weekly intervals or longer Maximum dose: Prandial dose: 4 mg Total daily dose: 16 mg/day Renal dysfunction [CrCl 20-40 mg/dL]: Initial dose: 0.5 mg with careful titration Adverse Drug Reactions: Hypoglycemia Upper respiratory infections, bronchitis, sinusitis, rhinitis Nausea, diarrhea, constipation, vomiting, dyspepsia Headache, chest pain Significant Drug Interactions: CYP2C8 inhibitors: may inhibit repaglinide metabolism CYP3A4 inducers: may increase repaglinide metabolism Gemfibrozil: may increase glucose levels and inhibit metabolism; avoid concomitant use Other interactions are similar to the sulfonylureas
Copyright 2011 American Society of Consultant Pharmacists
Meglitinides
Nateglinide [Starlix] Indications: Adjunct to nutrition and exercise to lower blood glucose in patients with type 2 diabetes who have not met goals through lifestyle changes Use in combination with metformin or thiazolidinedione Contraindications/Precautions: Patients with ketoacidosis and/or type 1 diabetes Increased risk of hypoglycemia in the elderly or debilitated Secondary failure may occur in prolonged therapy Mechanism of Action: Similar to repaglinide. Peak action: -1 hour Duration of action; half-life: 1 hour Metabolites: inactive Excretion: urine 16% excreted unchanged Dosing Administer 1-30 minutes before meals Similar to repaglinide, an extra dose of nateglinide should be added or omitted if an additional meal is eaten or skipped. Initial and maintenance: 120 mg three times daily as monotherapy or in combination with metformin or thiazolidinedione If A1C is close to goal the dose can be reduced to 60 mg three times daily
Copyright 2011 American Society of Consultant Pharmacists
Meglitinides
Adverse Drug Reactions: Hypoglycemia Upper respiratory infections Dizziness, diarrhea, back pain Jaundice, cholestatic hepatitis, elevated liver enzymes Significant Drug Interactions: Similar to the sulfonylureas and repaglinide Combination products: Repaglinide/Metformin
The meglitinides differ from sulfonylureas in their rapid peak and short half-life. This contributes to a reduced risk of hypoglycemia which may be beneficial in the elderly or those predisposed to hypoglycemia. In addition, these may be appropriate for the patient who eats only two meals a day or those with a varied meal plan such as patients with Dementia where meals may be erratic. Disadvantages of meglitinides include less reduction in the A1C and greater cost compared to sulfonylureas. This class also has the risk of secondary failure with prolonged use. Advantages include use as an alternative to sulfonyureas in patients with a true sulfa allergy and easier dosing with nateglinide compared to repaglinide because dose titration per se is not needed.
Biguanides Metformin
Indications: Monotherapy for those unable to achieve glycemic goals after a trial of diet and exercise. Combination therapy with oral agents and insulin Contraindications/Precautions: Contraindicated in males with serum creatinine >1.5 mg/dL and in females with serum creatinine >1.4 mg/dL; and in patients with abnormal creatinine clearance Acute or chronic metabolic acidosis Congestive heart failure class 3 or 4 Age >80 years, unless serum creatinine indicates normal renal function. Chronic alcohol intake Monitoring should include baseline serum creatinine with periodic follow-up testing Mechanism of Action: Primary: reduction of hepatic basal glucose production by suppression of gluconeogenesis and glycogenolysis Secondary: improve insulin stimulated glucose transport in skeletal muscle Peak action: 1-2 hours Half-Life: 1.5 -4.9 hours Metabolism: none Elimination: urine 90%
Biguanides Metformin
Dosing: Immediate Release [IR] Formulation [Glucophage] Initial dose: 500 mg or 850 mg once daily before the largest meal Dose titration: increase by 500 mg on a weekly basis up to 2500 mg/day. If using 850 mg tablets a three times daily schedule should be used. If using 1000 mg tablets it should be dosed twice daily In the elderly patient, metformin should not be titrated to maximum dose Extended Release [XR] formulation [Glucophage XR] Initial dose: 500 mg once daily with evening meal. Dose titration: 500 mg/week Maximum dose of 2,000 mg Adverse Drug Reactions Gastrointestinal side effects Diarrhea, nausea, vomiting Bloating, flatulence Anorexia and dysgeusia or altered taste Lactic Acidosis Occurs primarily in patients with predisposing conditions which may compromise renal function (e.g., MI, CHF, sepsis). Incidence: Rare; 0.03 cases/1000 patients-years of use Mortality rate: ~ 50% of cases result in death
Biguanides Metformin
Significant Drug Interactions Cationic drugs [eg. digoxin, amiloride, morphine , ranitidine, vancomycin]: may increase metformin serum levels Corticosteroids and estrogen: may decrease metformin effect when given with medications that can cause hyperglycemia Thiazides: may cause hyperglycemia
Available Combination Products Metformin/glipizide Metformin/glyburide Metformin/pioglitazone Metformin/rosiglitazone Metformin/repaglinide Metformin/sitagliptin The most common side effects of metformin are gastrointestinal in nature. While these can be problematic, they are usually transient and resolve with continued therapy. Administering metformin with meals and gradual dose titration can reduce the occurence of of these side effects. Metformin may not be appropriate in elderly patients which Gastrointestinal disorders such as Irritable Bowel Syndrome or Crohns Disease because it may worsen the bowel dysfunction. Patient education should include the reason for slow dose titration, take with meals, inform their healthcare provider if diarrhea or other intolerable side effects occur. Metformin XL may be an option in those who experience diarrhea.
Biguanides Metformin
Metformin can result in improvements in the lipid profile, specifically in triglycerides and the low-density lipoprotein fraction. Unlike the thiazolidinediones and sulfonyllurea agents, metformin is unlikely to cause weight gain, and many patients will have mild weight loss. Although it is rare, the most serious potential side effect of metformin use is lactic acidosis which can occur in patients with risk factors such as renal dysfunction. For this reason, metformin is contraindicated in patients with predisposing conditions such as cardiovascular collapse, acute myocardial infarction, severe infection, use of iodinated contrast media in radiologic tests, and major surgical procedures. Other risk factors for lactic acidosis include liver dysfunction, a history of alcohol abuse or binge drinking, and acute or chronic metabolic acidosis. Metformin should be stopped in patients undergoing major surgery. Therapy can be resumed post-procedure after oral intake resumes and renal function is normal. This should be discussed with the patient prior to procedures so he/she is aware that it will be stopped temporarily and they should keep in contact with their prescriber regarding when it is appropriate to resume
Thiazolidinediones (TZDs)
Indications Use alone, or in combination with insulin, sulfonylurea, metformin, sitagliptin Treatment of polycystic ovarian syndrome Contraindications/Precautions Contraindicated in patients with Heart Failure Class III or IV Active liver disease or serum ALT concentrations of more than 2.5 times the upper limit of normal [ULN]. Discontinue TZD if ALT is more than 3 times the ULN on therapy. TZDs may cause pre-menopausal women who are insulin resistant and anovulatory. These patients may be at risk for pregnancy if contraception methods are not used. Reduction in hemoglobin and hematocrit possibly due to volume expansion. This may occur within the first 4-8 weeks and persist for at least 2 years. Percent reduction varies with the TZD used. Monitor Liver Function at baseline and every 2 months for the first 12 months, then periodically thereafter
Thiazolidinediones (TZDs)
Mechanism of Action: Primary improve glycemic control by increasing insulin sensitivity through direct stimulation of the peroxisomeproliferator-activated receptor-gamma [PPAR ] on the nuclear surface of cells responsible for modulating lipid homeostasis, adipocyte differentiation, and insulin action. Secondary - decreased hepatic glucose production Peak concentration: Pioglitazone: 2 hours, Rosiglitazone: 1 hour Elimination: pioglitazone - urine 15-30%; rosiglitazone urine 64%; feces 23% Half-life: pioglitazone 16-24 hours; rosiglitazone 103-158 hours
Dosing Rosiglitazone [Avandia] Initial dose: 4 mg once daily or 2 mg twice daily Dose titration: after 8-12 weeks the dose may be increased to 8 mg given once daily or 4 mg twice daily [twice daily dosing may be more effective than once daily dosing] Maximum dose: Monotherapy or with metformin: 8 mg/day In combination with insulin or sulfonylurea: 4 mg/day. Adjust insulin dose as needed based on glucose response
Copyright 2011 American Society of Consultant Pharmacists
Thiazolidinediones (TZDs)
Pioglitazone [Actos] Initial dose: 15 or 30 mg once daily Dose titration: in 8-12 weeks increase to a maximum dose of 45 mg once daily In combination therapy the maximum dose is 30 mg/day with a 10-25% reduction in insulin dose based upon glucose response Adverse Effects Weight gain, edema Upper respiratory infections, sinusitis Headache Anemia [pioglitazone] Changes in liver function tests Increased incidence of bone fractures in females Cardiovascular events [controversial at this time] New onset or worsening of diabetic macular edema [pioglitazone] Significant Drug Interactions Rosiglitazone Increased risk of hypoglycemia when administered with insulin or secretagogues Pioglitazone Estrogen and norethindrone: pioglitazone may reduce contraceptive efficacy Other interactions similar to rosiglitazone
Copyright 2011 American Society of Consultant Pharmacists
Thiazolidinediones (TZDs)
Available Combination Products Pioglitazone/glimepiride Pioglitazone/metformin Rosiglitazone/glimepiride Rosiglitazone/metformin Thiazolidinediones can be used as monotherapy or in combination with sulfonylureas, metformin, or insulin [pioglitazone]. As with other oral agents, the degree of A1C reduction required is a consideration when selecting pharmacotherapy. Metformin and sulfonylureas provide a slightly greater benefit in A1C reduction than the TZDs and may be a cost-effective choice. Recently several studies have suggested a link between TZDs and reductions in bone density and fractures. The use of TZDs in patients at risk for osteoporosis may result in an increased fracture rate. This should be considered if these are prescribed in elderly patients, especially females. The TZDs have differing effects on the Lipid profile. Pioglitazone is associated with reductions in triglyceride levels and increases in HDL. However, both agents can raise the LDL. Another recent development related to the TZDs are conflicting reports of cardiovascular mortality in patients receiving rosiglitazone. Several meta-analyses have suggested a 30-40% relative increase in risk for myocardial infarction with rosiglitazone. In comparison, the Prospective Pioglitazone Clinical Trial in macrovascular events [PROactive] did not demonstrate significant effects of pioglitazone compared to placebo on the primary cardiovascular outcome after 3 years of follow-up. Pioglitazone was associated with a 16% reduction in death, myocardial infarction and stroke [a secondary endpoint reported to have marginal statistical significance]. Meta-analyses have supported a possible beneficial effect of pioglitazone on cardiovascular risk. Recently, the American Diabetes Association [ADA] and the European Association for the Study of Diabetes [EASD] released a Consensus Statement Update advising against use of rosiglitazone since other options are available.
Copyright 2011 American Society of Consultant Pharmacists
The DPP-4 inhibitors are new agents in the management of type 2 diabetes. They can be used in combination with other oral agents or as monotherapy.. Because of the potential reduction in A1C when compared to the other oral agents, these may be appropriate for individuals with A1C values close to 7%. They appear to be well-tolerated and can be used in patients with renal insufficiency. Once-daily dosing is beneficial in terms of adherence. The place in diabetes management for these new agents has not been established and cost will likely be an issue in prescribing. Until additional safety data is available, medications with long-standing safety data may be preferable.
Alpha glucosidase inhibitors are not widely used because the gastrointestinal side effects are not well-tolerated by most patients. In clinical trials, 25-45% of patients discontinued the alpha-glucosidase inhibitor because of this side effect. In addition, other available oral options for diabetes management provide greater reduction in the hemoglobin A1C and improved tolerance.
Human Insulin
Recombinant DNA Human insulin has essentially made animal source insulin obsolete. Insulin works by promoting the uptake of glucose, fatty acids, and amino acids by the liver and peripheral tissues. Side effects include weight gain, hypoglycemia, lipoatrophy, and lipodystrophy. There are numerous insulin formulations from which to choose when designing an insulin regimen. The tables in 07.02.08 provide a summary of the pharmacokinetic properties of the available products, physical characteristics, and injection devices available. It is important to understand the kinetics of the selected insulin formulation[s] when designing a pharmacotherapy plan, interpreting fingerstick and plasma glucose results, adjusting insulin doses, and minimizing side effects.
Insulin Characteristics
Insulin Characteristics
Prandial insulin products include regular insulin and several rapid-acting insulins. The latter offer the advantage of more rapid onset of action which permits a more flexible injection time in relation to the meal. These products can be injected within 10-15 minutes prior to or within 15 minutes of beginning to eat in comparison to regular insulin or combinations with regular insulin which should be injected 30-45 minutes prior to eating. The one drawback to the rapid acting insulin formulations is that they can be mixed with NPH insulin but not with insulin glargine or insulin detemir. When prandial insulin is used with insulin glargine or insulin detemir, multiple daily injections will be required. This should be discussed with the patient and their preferences taken into consideration before deciding on an insulin regimen. The intermediate-acting insulin NPH provides dosing flexibility and is available as a fixed combination or single-entity product. When administered as a mixed dose in combination with regular insulin it must be injected 30-45 minutes prior to eating. If the regimen is composed of NPH and a rapid-acting insulin analog, it can be injected in the same timeframe discussed for rapid-acting analogs and can be mixed in the same syringe with NPH. Long acting basal insulin formulations include insulin glargine [Lantus] and insulin detemir [Levemir]. Insulin glargine does not have a peak action; it provides a basal release of insulin and is administered once daily. There is no additional benefit gained in A1C control by administering insulin glargine more than once daily. In comparison, insulin detemir has a peak action and 1-2 injections may be required to achieve glycemic control targets. A potential benefit of insulin detemir is less effect on weight and less intra-patient variability in glycemic response. Unlike NPH insulin, insulin glargine and insulin detemir are clear.solutions. When used in combination with prandial insulin products, there is the potential for medication errors because of administering the incorrect insulin. Patients must be instructed to store the clear insulin products in separate areas or to develop their own system to prevent this potentially dangerous mix-up. Similar to the rapid-acting analogs, insulin glargine and detemir cannot be mixed or diluted with any other solution or any other type of insulin. When converting to insulin glargine from NPH, the glargine dose should be started at 80% of the total NPH dose and administered once daily. Copyright 2011 American Society of Consultant Pharmacists
Insulin Products
Retrieved 8/1/09 from https://secure.pharmacytimes.com/lessons/200510-03.asp Copyright 2011 American Society of Consultant Pharmacists
Insulin Products
The above chart provides a summary of available insulin products. When selecting an insulin formulation for the elderly patient, the regimen must be tailored to the persons cognitive skills, risk of hypoglycemia, social and economic factors, renal function, and visual or dexterity impairments. When financial issues are a concern, NPH insulin is a cost-effective, intermediate-acting, alternative. However, in the elderly with renal insufficiency who require a prandial insulin, a rapid-acting analog should be considered rather than Regular insulin because their excretion is not as dependent on renal function. Often, it is necessary to only use a basal or intermediate acting formulation without a prandial insulin if hypoglycemia or mental status are a concern. It may also be necessary to use an injection device; this too must be one that the patient or caregiver is able to manipulate. Caregivers may have to calculate prandial insulin dose when used in combination with NPH; in this scenario a fixed-mixed product may be the optimal choice to promote a simplified regimen and adherence. Either of these scenarios may necessitate a less aggressive A1C goal. Of note, Lente and Ultralente insulin are no longer available.
Insulin Products
Indications: Adjunctive therapy to treat type 2 diabetes for patients who have not achieved glycemic goals on a regimen of: Metformin A sulfonylurea A combination of metformin and sulfonylurea A combination of metformin and a thiazolidinedione Contraindications/Precautions: Patients with type 1 diabetes ot those with diabetic ketoacidosis Exenatide is not a substitute for insulin Severe GI disease, especially those with gastroparesis or a history of bowel obstruction Patients with severe renal impairment [CrCl <30 ml/min] or End-Stage Renal Disease should not receive exenatide Mechanism of Action: Exenatide is an incretin mimetic which enhances glucose-dependent insulin secretion by pancreatic -cells and restores first-phase insulin response. During hyperglycemia, exenatide lowers serum glucagon concentrations which results in reduced hepatic glucose release and decreased insulin need Gastric-emptying is delayed, thus reducing meal-related glucose excursions Food intake is reduced It is recommended that sulfonylurea dose reduction is considered when exenatide is initiated
Figure 1Algorithm for the metabolic management of type 2 diabetes. Reinforce lifestyle intervention at every visit. Check A1C every 3 months until 7% and then at least every 6 months. Associated with increased risk of fluid retention, CHF, and fractures. Rosiglitazone, but probably not pioglitazone, may be associated with an increased risk of myocardial infarction. Although three oral agents can be used, initiation and intensification of insulin therapy is preferred based on effectiveness and lower expense. Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy. Diabetes Care 31: 173-175, 2008 by the American Diabetes Association, Inc., and Springer. Copyright 2011 American Society of Consultant Pharmacists
Medication recommendations include daily aspirin [if no contraindications], administration of an angiotensin converting enzyme inhibitor [ACEI] or an angiotensin receptor blocking agent [ARB], Nutrition Education and Diabetes SelfManagement Education and Training when indicated. While we may be limited in the choice of diabetes medications, there are many non-pharmacologic options available to improve quantity and quality of life in the elderly patient with diabetes. A thorough Pharmacotherapy plan for the elderly patient must include all aspects of diabetes management.
Resources
American Association of Clinical Endocrinology. http://www.aace.com/clin/guidelines/diabetes2007.pdf American Association of Diabetes Educators, http://www.diabeteseducator.org American Diabetes Association. Position Statement. Standards of Medical Care in Diabetes. Diabetes Care 32:S13S61, 2009 by the American Diabetes Association The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), http:// www2.niddk.nih.gov U.S. Food And Drug Administration Approves ONGLYZA (saxagliptin) For The Treatment Of Type 2 Diabetes Mellitus In dults. Retreived 8/1/09 from http://www.medicalnewstoday.com/articles/159538.php. For more information: American Association of Clinical Endocrinologists. Medical Guidelines for Clinical Practice for The Management of Diabetes Mellitus. Endocrine Practice 2007. 13 [suppl 1], May/June 2007. The Action to Control Cardiovascular Risk in Diabetes Study Group*. Effects of Intensive Glucose Lowering in Type 2 Diabetes. N Engl J Med 2008;358:2545-59. Chau D, Edelman SV. Clinical management of diabetes in the elderly. Clinical Diabetes 2001 19[4]:172-75. Dormandy JA, Charbonnel B, Eckland DJ, et al; the PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279-1289. Drab SR, Meece J, Garza H. The 3 Rs of managing seniors with type 2 diabetes: recognition, risks, and remedies. The Consultant Pharmacist 2009 June;24:1-24.
Copyright 2011 American Society of Consultant Pharmacists
Resources
Hirsch IB. Drug therapy: Insulin analogues. N Engl J Med 2005;352:174-183. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD): study design and protocol. Diabetologia. 2005;48:1726-1735. McEvoy GK, ed. Insulin human and insulin analogue. In: American Hospital Formulary Service. Bethesda, MD: American Society of Health-System Pharmacists; 2005: 2970-2980. retrieved May 3 2009 from https:// secure.pharmacytimes.com/lessons/200510-03.asp Mensing C, editor; Cypress M, Halstenson C, McLaughlin S, Walker EA, section editors. The art and science of diabetes self-management education. Illinois: American Association of Diabetes Educators; 2006. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, et al. Medical management of hyperglycemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2009 Oct 22;52:17-30. Neumiller JJ, Setter SM, Gates BJ, Sonnett TE, Dobbins EK, Campbell K. Pharmacological management of glycemic control in the geriatric patient with type 2 diabetes mellitus. Consult Pharm. 2009 Jan;24(1):45-63 White J R, Campbell RK. ADA/PDR medications for the treatment of diabetes. Montvale [NJ]: American Diabetes Association and Thomson Reuters, Healthcare; 2008. Neumiller JJ, Setter SM, Gates BJ, Sonnett TE, Dobbins EK, Campbell K. Pharmacological management of glycemic control in the geriatric patient with type 2 diabetes mellitus. Consult Pharm. 2009 Jan;24(1):45-63
Learning Objectives
By the end of this Review Concept you should be able to: Describe the influence of aging on thyroid hormone production and clearance. Classify an elderly patient as either hyper- or hypo- thyroid based on symptoms, signs and other objective data. Construct a treatment plan for an elderly patient with either hyperthyroid of hypothyroid given a patient case. Discuss the subclinical forms of hyperthyroidism and hypothyroidism. List the various types of drug-drug interactions that can occur with L-thyroxine replacement therapy.
Figure 1 depicts the classical negative feedback system for maintaining normal circulating concentrations of thyroid hormones. Thyrotropin-releasing hormone (TRH) is secreted by the hypothalamus and stimulates the anterior pituitary to synthesize and release thyrotropin, which is commonly referred to as thyroid-stimulating hormone or TSH. The released TSH stimulates the thyroid gland to synthesize and secrete the thyroid hormones thyroxine and triiodothyronine, often abbreviated as T-4 and T-3 respectively. Some of the released thyroxine enters the liver where is deiodinated to triiodothyronine, which enters the circulating blood. Approximately 80 % of the circulating T-3 is derived from the hepatic conversion of T-4 to T-3. When adequate circulating concentrations of thyroid hormones are achieved, these hormones feedback negatively to suppress the further release of TRH and TSH. As circulating concentrations of thyroid hormones decline, TRH and TSH are sequentially released to stimulate the release of T-4 and T-3. Biologically, T-3 is about 4 times more potent than T-4.
Copyright 2011 American Society of Consultant Pharmacists
Figure 2 shows the normal euthyroid state, where TSH is secreted by the pituitary gland and stimulates the thyroid gland to release T-4 and T-3, which in turn feedsback negatively on pituitary TSH secretion.
Figure 3 depicts the situation where the thyroid gland is failing to secrete adequate amount of T-4 and T-3. The resulting lower serum concentrations of thyroid hormones have impaired their negative feedback on pituitary TSH release. Therefore, serum TSH concentrations will rise progressively as thyroid gland failure advances in severity. This is referred to as primary gland failure.
Figure 4 shows the situation where the anterior pituitary gland is losing its capacity to secrete TSH. Diminishing TSH secretion is paralleled by diminishing release of T-4 and T-3 from the thyroid gland. This progressive form of thyroid gland failure secondary to pituitary failure will eventually result in overt hypothyroidism. This form of hypothyroidism is referred to as central or secondary hypothyroidism.
Figure 5 shows a situation where the entire thyroid gland is autonomously secreting excessive amounts of T-4 and T-3 due to a diffusely enlarged gland, as in Graves disease or toxic goiter. Discrete nodules may also autonomously secrete excessive amounts of T-4 and T-3. The excess secretion of T-4 and T-3 will markedly suppress pituitary TSH secretion.
During chronic drug administration, the elimination half-life of a medication is the prime determinant of the time required to achieve a steady-state drug concentration. Medications must be administered for 4 - 5 drug half-lives in order to reach plateau serum drug concentrations. When considering levothyroxine replacement therapy in the elderly, its protracted half-life of 9 days mandates about 4 - 6 weeks of daily therapy to achieve a steady-state serum thyroxine concentration. Thus it is best to evaluate the effects of a dosage adjustment in levothyroxine therapy only after 4 - 6 weeks of continuous use. Because the capacity to metabolically inactivate thyroxine continuously declines with aging, the levothyroxine dose used as replacement therapy will often need to be adjusted downward as the patient advances from young elderly to very elderly.
Hypothyroidism: Definition Low serum concentrations of thyroxine and triiodothyronine due to a hypofunctioning thyroid gland. Incidence In the Framingham study, the prevalence in patients over 60 years of age was 5.9 % in women and 2.3 % in men. In a general population, the incidence of autoimmune hypothyroidism (most common cause) is about 0.4 % in women and 0.1% in men. The risk for hypothyroidism increases with aging.
Hyperthyroidism is almost always associated with a suppressed serum TSH and elevated serum free T-4 and T-3 concentrations. Hypothyroidism due to primary gland failure is associated with an elevated serum TSH concentration and a low serum free T-4 level. Serum total T-3 concentrations are not helpful in diagnosing hypothyroidism because many non-thyroidal illnesses or conditions decrease its concentration. Serum TSH levels are not useful in suspected hypothyroid patients who have underlying pituitary dysfunction.
Causes of Thyrotoxicosis
Graves Disease Toxic multinodular goiter (TMNG) Toxic adenoma Thyroiditis Iodide-induced (Jod-Basedow effect, mostly occurring in patients with underlying nontoxic multinodular goiter when given iodide containing medications TSH-secreting pituitary adenoma Oversupplementation with thyroid hormone replacement therapy
The most common causes of hyperthyroidism in the elderly are Graves disease and TMNG, with an approximate equal distribution. The administration of iodide containing medications to patients with underlying Graves disease or a multinodular goiter may precipitate acute hyperthyroidism. Oversupplementation with levothyroxine may produce exogenous hyperthyroidism, which is easily managed with a dose reduction of levothyroxine.
Many of the common signs and symptoms of hyperthyroidism are not manifest in the elderly. It has been estimated that only about one-third of elderly patients present with typical features of thyrotoxicosis. Many aged patients who are hyperthyroid exhibit anorexia, weight loss, weakness and proximal muscle wasting leading to a masked or apathetic form of the disease. Cardiac signs are more apparent in the elderly and include atrial fibrillation, angina and refractory heart failure and may be the only presenting signs of hyperthyroidism. Thyrotoxic atrial fibrillation should be treated with anticoagulants to avoid the risk of an embolic event. Psychiatric manifestations of confusion, agitation and dementia may predominate in aged patients. Hyperthyroidism accelerates bone loss in the elderly and may lead to severe osteoporosis with an attendant risk of fractures. In the majority of aged patients the thyroid gland is nonpalpable and the classic eye signs are absent.
Treatment of Hyperthyroidism
Radioactive iodide (ablative therapy) Thioamides Surgery (ablative therapy) Iodides Beta-adrenergic blockers and calcium channel blockers
There are several treatment options for hyperthyroidism. The treatment of choice for elderly patients with either Graves disease or toxic multinodular goiter is radioactive iodide (131 I). This therapy provides a definitive cure. Radioactive iodide is administered orally as the sodium salt in an aqueous solution or a capsule. Once incorporated in the thyroid gland, radioactive iodide slowly destroys it, requiring from 6-18 weeks to induce an euthyroid state. The destruction of the thyroid gland continues indefinitely and hypothyroidism should be an expected outcome of treatment. Salivary gland inflammation and neck pain are potential adverse effects of radioactive iodide (131 I) therapy. In addition, there is recent evidence that radioactive iodine treatment may precipitate hyperparathyroidism, with elderly patients appearing more susceptible to this effect than a younger age group. It is recommended that serum or ionized calcium be measured every 2-3 years in all elderly patients who are treated with radioactive iodine. Thioamides can also be used as primary therapy in elderly patients. Surgery is rarely performed in elderly patients, but may be necessary for patients with toxic goiters causing airway obstruction or swallowing problems. Preoperative administration of iodides (usually Lugols solution or saturated solution of potassium iodide) is common and has been shown to reduce thyroid vascularity and intraoperative blood loss during thyroidectomy. Complications of surgery include hypothyroidism, hypoparathyroidism, laryngeal nerve injury, bleeding, jugular vein or carotid artery injury, and infections. Beta-adrenergic blockers or calcium channel blockers may be used to attenuate some of the sympathomimetic-like features of hyperthyroidism.
Copyright 2011 American Society of Consultant Pharmacists
Hyperthyroid elderly patients should be made euthyroid with thionamide therapy prior to the use of radioactive iodide. Radiation-induced thyroiditis is sometimes a complication of radioactive iodide therapy, resulting in the uncontrolled release of stored thyroid hormones and a brief worsening of the thyrotoxic state. This complication is reduced significantly if the patient is rendered euthyroid before radioactive iodide therapy is initiated. Elderly patients with hyperthyroidism due to Graves disease or toxic multinodular goiter can be restored to a euthyroid state with thioamides alone. This form of therapy is not curative in patients with toxic multinodular goiter and life long treatment will be necessary. In patients with Graves disease there can be a high rate of relapse with stopping the thionamide after a year of use. All patients taking thionamides must be warned of the small risk of agranulocytosis and to immediately contact their physician if they develop a sore throat, mouth sores, or fever and obtain a white blood cell count. Thionamide-induced agranulocytosis is rapidly reversible when the medication is stopped. Filgrastim administration does not improve recovery outcome.
Subclinical hyperthyroidism
Subclinical hyperthyroidism Defined as a suppressed serum TSH concentration and a normal free serum thyroxine level. Serum triiodothyronine (T-3) must be also be measured to rule out T-3 thyrotoxicosis. Estimated population prevalence of 0.9%; more common in women. Certain nonthyroidal illnesses may also suppress serum TSH concentrations and must be ruled out. In patients without thyroid nodules, suppressed serum TSH may normalize in about 50% of cases. However, in patients with autonomous thyroid nodules, spontaneous normalization of the serum TSH is unusual and advancement to overt hyperthyroidism is considered a strong possibility. Risk of new onset atrial fibrillation, accelerated bone loss and dementia is increased. Decision to treat should be based on the presence of symptomology (weight loss, psychiatric problems, fatigue) and risk for exacerbating underlying medical problems (osteoporosis, cognitive loss and heart disease). Elderly patients may be treated initially with a thionamide, usually methimazole at a dose of 5 10 mg daily. Successful resolution of symptoms indicates a consideration of ablative therapy with radioiodide. If you suspect that subclinical hyperthyroidism is contributing to progressive osteoporosis, cognitive loss and heart disease in the older patient, ablative therapy with radioiodide should be discussed with the patient and family.
Subclinical hyperthyroidism
Many endocrinologists consider subclinical hyperthyroidism to be the mildest form of hyperthyroidism. The key serum chemistries are a suppressed TSH concentration and normal thyroid hormone levels. Remember that the range for what is considered a normal serum thyroxine concentration is quite wide, from 5 to 12 micrograms per deciliter. Consider a normal or euthyroid woman who requires a serum thyroxine concentration of 7 micrograms per deciliter for maintaining a desired metabolic state, and which is confirmed by a normal serum TSH concentration. If in this individual the serum thyroxine concentration now rises to 10 micrograms per deciliter because of the development of an autonomously functioning thyroid nodule, she is still in the normal range of serum thyroxine levels, but this level is too high for her metabolic wellbeing, and this is reflected by a suppressed serum TSH concentration. A scan of the thyroid gland would reveal the nodule and treatment would be indicated if this patient manifested symptoms of weight loss, psychiatric problems, fatigue or risk for aggravating underlying medical problems such as osteoporosis, cognitive loss and heart disease.
Cause of Hypothyroidism
Primary thyroid gland failure: Laboratory findings: low serum concentrations of thyroxine and triiodothyronine and an elevated serum TSH level. Etiologies: Autoimmune destruction (Hashimotos or atrophic thyroiditis) Prior ablative therapy with radioactive iodide (131 I) Subtotal or total thyroidectomy Prior radiation therapy to the neck Medications: amiodarone, iodides, lithium, Iodine deficiency Infiltratrative disorders: amyloidosis, sarcoidosis, Scleroderma Pituitary TSH deficiency (secondary or central hypothyroidism): Laboratory findings: low serum concentrations of thyroxine and triiodothyronine and a normal or reduced serum TSH level Etiologies: Hypopituitarism: tumors, prior surgery/radiation, trauma and infiltrative disorders Hypothalamic dysfunction: tumors, trauma and infiltrative disorders
Cause of Hypothyroidism
The two major categories of hypothyroidism are primary thyroid gland failure and anterior pituitary gland failure. Autoimmune destruction of the thyroid gland is the most common cause of primary hypothyroidism. Autoimmune destruction of the thyroid gland may occur in association with other autoimmune disorders including pernicious anemia, Addisons disease, multiple sclerosis, and celiac disease. Because the association is particularly strong for pernicious anemia, it is reasonable to screen all elderly patients with a documented or suspected diagnosis of autoimmuneinduced hypothyroidism for vitamin B-12 deficiency. Destruction of the thyroid gland by radiation, often from prior treatment of hyperthyroidism with radioactive iodide (131 I), is also another common cause of primary gland failure. Lithium treatment can cause hypothyroidism primarily by inhibiting the release of thyroid hormones from the gland. Its incidence varies widely, with overt hypothyroidism being reported in up to 20% of patients. Exposure to iodides, usually from radiocontrast agents or from the deiodination of amiodarone, can in susceptible patients cause hypothyroidism. In normal individuals, excessive exposure to iodides will transiently inhibit the release of thyroid hormones from the gland. However, in patients who have underlying subclinical thyroid gland injury or dysfunction, iodide exposure can induce persistent hypothyroidism. Anterior pituitary gland failure will cause hypothyroidism secondarily due to the loss of TSH secretion. This type of hypothyroidism is referred to as secondary or central hypothyroidism.
The signs and symptoms of hypothyroidism are many and varied, develop insidiously, touch upon many subspecialties in medicine and in the elderly are often attributed to the aging process. Nonspecific symptoms such as dry skin, constipation, joint complaints, weakness, and depression are common in the elderly and do not arouse suspicion of an underlying thyroid illness. Global effects of hypothyroidism in the elderly may present as nonspecific as apathy or as a general failing in mobility. Classic features of hypothyroidism occur in the elderly and include periorbital and peripheral edema (myxedema), bradycardia, hypothermia, and hoarseness, and demand immediate attention. All hypercholesterolemic patients should be evaluated for hypothyroidism. Yearly screening of a serum TSH concentration is very helpful in identifying thyroid problems in the elderly.
There are two gastrointestinal disorders that may significantly impair the bioavailability of orally administered levothyroxine. These include celiac disease, which is an autoimmune disorder that causes villous atrophy in the small intestine, and atrophic gastritis, which is caused by parietal cell autoantibodies or chronic H pylori infection. Hypothyroid patients who are maintained euthyroid on unusually large daily doses of levothyroxine should be accessed for these gastrointestinal pathologies.
Subclinical Hypothyroidism
Defined as an elevated serum TSH and a normal serum free thyroxine concentration. An estimated population prevalence of 8.5%; more common in women and with aging; in women and men over 74 years of age, a prevalence of 21% and 16% respectively was reported in the Colorado Thyroid Disease Prevalence Study. Although most patients have no obvious cause for subclinical hypothyroidism, certain risk factors have been identified and include prior treatment with neck irradiation, type I diabetes mellitus, primary adrenal insufficiency, and medications that may inhibit thyroid gland function (amiodarone, interferon alpha and lithium). The risk for advancement to overt hypothyroidism is increased in patients with serum TSH concentrations above 10 mU/L or positive titers for serum thyroid autoantibodies against thyroperoxidase (also referred to as antiTPO or antimicrosomal antibodies). Treatment to normalize serum TSH with thyroxine supplementation is advised if: 1. The serum TSH is greater than 10 mU/L 2. Anti-TPO antibodies are present 3. Signs and symptoms consistent with hypothyroidism are present and troublesome 4. Goiter or hypercholesterolemia is present
Subclinical Hypothyroidism
Levothyroxine supplementation for subclinical hypothyroidism in the elderly should begin low at 12.5 or 25 mcg daily because of the risk of associated with evident or occult heart disease. A serum TSH concentration should be measured 4 - 6 weeks after initiating thyroxine therapy. The dose of levothyroxine needed normalize the serum TSH concentration is usually lower that that needed to treat overt hypothyroidism. Levothyroxine requirements may increase over time, as further progression to thyroid failure is possible.
Drug interactions involving levothyroxine replacement therapy occur frequently in the elderly. Osteoporosis and iron deficiency anemia from chronic blood loss are common in this age group, thus increasing the probability that calcium or iron supplements will be co-administered with levothyroxine. These interactions can be avoided by always administering the levothyroxine product first and then waiting at least 2 hours before giving the interfering iron or calcium preparation. Drugs that increase the metabolic degradation of thyroid hormone, often referred to as enzyme inducers, will also increase levothyroxine requirements. Whenever enzyme inducers are started or stopped in patients on levothyroxine therapy, it is important to obtain a serum TSH concentration 6-8 weeks later. With enzyme-inducers, the induction process reaches a steady-state after about 2 weeks of inducer administration. Similarly, when an enzyme-inducer is stopped it take about 2 weeks to fully deinduce. Always suspect a levothyroxine drug interaction in elderly patients taking doses of 150 mcg or greater per day. The dosage range for levothyroxine replacement in the elderly is usually 50 125 mcg per day. The larger doses are often needed for the heavier patients.
There are a number of drugs that interact with levothyroxine therapy. These drugs include a number of agents that decrease the intestinal absorption of levothyroxine. Additionally, amiodarone has been found to decrease T4 conversion to T3.Phenytoin, phenobarbital, carbamazepine and rifampin have been found to accelerate the hepatic clearance of T-4, resulting in lower serum thyroid hormone concentrations. Orally administered estrogens stimulate the hepatic production of thyroid binding proteins and thus may increase levothyroxine requirements by reducing the unbound serum hormone concentrations. You may need to decrease levothyroxine supplementation therapy when co-administered drugs that interfere with its bioavailability, induce its hepatic clearance or augment its serum protein bind are discontinued.
Resources
Arafah BM. Increased Need for Thyroxine in Women with Hypothyroidism during Estrogen Therapy. N Eng J Med 2001; 344: 1743 49. Arafah BM. Decreased L-thyroxine Requirement in Women with Hypothyroidism During Androgen Therapy for Breast Cancer. Ann Intern Med 1994;121:247-51.. Blakesley V, Awni W, Locke C et al. Are Bioequivalence Studies of Levothyroxine Sodium Formulations in Euthyroid Volunteers Reliable? Thyroid 2004;14:191- 200. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado Thyroid Disease Prevalence Study. Arch Intern Med 2000;160:526. Checchi S, Montanaro A, Pasqui L et al. L-Thyroxine Requirement in Patients with Autoimmune Hypothyroidism and Parietal Cell Antibodies. J Clin Endocrinol Metab 2008;93:465-469. Clyde PW, Harari AE, Getka, EJ, Shakir KMM. Combined Levothyroxine Plus Liothyronine Compared with Levothyroxine Alone in Primary Hypothyroidism. JAMA 2003;290:2952-58. Colaco SM, Ming MS, Reiff E et al. Hyperparathyroidism After Radioactive Iodine Therapy. Am J Surg. 2007;194:323-27. Cooper DS. Subclinical Hypothyroidism. N Engl J Med 2001;345:260-5.
Resources
Hornick TR, Kowal J. Clinical Epidemiology of Endocrine Disorders in the Elderly. Endocrinology and Metabolism Clinics of North America. 1997;26:145 Huber G, Staub J-J, Meier C et al. Prospective Study of the Spontaneous Course of Subclinical Hypothyroidism: Prognostic Value Of Thyrotropin, Thyroid Reserve, and Thyroid Antibodies. J Clin Endocrinol Metab 2002;87:3221-5. Jenkins RC, Weetman AP. Disease Associations with Autoimmune Thyroid Disease. Thyroid 2002;12:977-88. Kalmijn S, Mehta KM, Pols HAP, et al. Subclinical Hyperthyroidism and the Risk of Dementia. The Rotterdam Study. Clinical Endocrinol 2000;53:733-7. Mandel SJ, Brent GA, Larsen PR. Levothyroxine Therapy in Patients with Thyroid Disease. Ann Intern Med 1993;119:492-502. McDermont JH, Cos A, Walsh CH. Celiac Disease Presenting as Resistant Hypothyroidism. Thyroid 2005;15:386-388. Surks MI, Ortiz E, Daniels GH, et al. Subclinical Thyroid Disease. Scientific Review and Guidelines for Diagnosis and Management. JAMA. 2004;291:228-38. Surks MI, Sievert R. Drugs and Thyroid Function. New Engl J Med. 1995;333:1688-94. Thomas FB, Mazzaferri EL, Skillman TG. Apathetic Thyrotoxicosis: A Distinct Clinical and Laboratory Entity. Ann Internal Med 1970;72:579-85.
Resources
Toft AD. Subclinical Hyperthyroidism. N Engl J Med 2001;345:512-6. Utiger RD. Estrogen, Thyroxine Binding in Serum, and Thyroxine Therapy. N Engl J Med 2001;344:1784-5. Walsh JP, Shiels L, Lim EM et al. Combined Thyroxine / Liothyronine treatment dose not improve well-being, quality of life or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. J Clin Endocrinol Metab. 2003;88:4543-55. Websites: American Thyroid Association Thyroid Disease Manager FDA Electronic Orange Book
By the end of this Review Concept you should be able to: Describe the effects of aging on the HPA (hypothalamic pituitary adrenal) axis and the adrenal glands. Classify an elderly patient as having either Cushings disease or Addisons disease based on clinical presentation and laboratory values. Construct a treatment plan for an elderly patient with either Cushings disease or Addisons disease, given a patient case.
Adapted from: Nieman LK, Orth DN. Clinical Manifestations, Diagnosis, and Treatment of Adrenal Insufficiency. UpToDate Online.
Each of the two glands is located extraperitoneally to the upper poles of each kidney. Adrenal medulla (10% of gland) secretes catecholamines.
Spontaneous or Pituitary Cushings syndrome most commonly affects young and middle-aged adults; however, it can strike in the later years. Only about five to twenty-five out of every million people are affected each year. Ectopic Cushings, which occurs secondary to tumors, affects a larger percentage of older adults.
A common cause of cortisol excess in the elderly is secondary to supraphysiologic doses of glucocorticoid medications such as prednisone use in COPD patients or rheumatoid arthritis patients. When assessing a patient for suspected iatrogenic Cushings disease it is important to ascertain both the total daily dose and the length of time the individual has been exposed to exogenous glucocorticoids. Doses greater than 20 mg of prednisone a day for longer than 3 weeks can result in hypothalamic pituitary axis suppression.
When the excessive circulation of cortisol is the result of overproduction by the bodys own adrenal glands - pituitary adenomas and other kinds of tumors are usually at fault. Cushings Disease is caused by a pituitary adenoma which secretes increased amounts of adrenocorticotropin or A-C-T-H, a hormone that stimulates the adrenal glands to release cortisol into the bloodstream. Ectopic ACTH Syndrome is caused by a tumor that secretes ACTH, which in turn stimulates the release of cortisol from the adrenal glands. Iatrogenic Cushings Syndrome is caused by the administration of supraphysiologic doses of glucocorticoid medications, resulting in suppression of the HPA axis. Adrenal tumors, though relatively rare, can also cause Cushings syndrome because they contain cancer cells that secrete increased amounts of cortisol along with other adrenal cortical hormones.
Comparison of Corticosteroids
The physiological dose of prednisone is roughly 5 mg per day. Iatrogenic Cushings syndrome can be caused by supraphysiologic doses of glucocorticoid medications. Not all corticosteroids have the same glucocorticoid and mineralocorticoid activity. For instance, the glucocorticoid activity of prednisone 20 mg is equivalent to 3 mg of dexamethasone.
Copyright 2011 American Society of Consultant Pharmacists
Hirsutism
Buffalo hump
Images from: http://vasculitis.med.jhu.edu/treatments/prednisone.html.
Abdominal Striae
The symptoms of Cushings syndrome vary. In younger individuals, the disease usually manifests as upper body or truncal obesity, including rounded face and increased fat around the neck, the so-called buffalo hump. The arms and legs become thinner, and the skin becomes fragile and thin. Purplish stretch marks may appear on the abdomen, thighs, buttocks, arms and breasts. The bones are weakened, and routine activities may lead to backaches or rib and spinal fractures. Other symptoms include severe fatigue, weak muscles, high blood pressure, and blood sugar. Irritability, anxiety and depression are also common. Women tend to exhibit excess hair growth and menstrual irregularity. Men have decreased fertility and libido.
Copyright 2011 American Society of Consultant Pharmacists
In Younger Patients: Upper body obesity Thinning arms and legs Thin and fragile skin Purplish stretch marks Weakened bones, muscles Severe fatigue Increased blood pressure Increased blood glucose Irritability, anxiety, depression
In Older Patients: Easy bruising, poor healing Falls, - risk of fractures Failure to thrive Refusal to eat, weight loss Confusion, dementia, paranoia Hypochondriasis, psychosis Compromised immune system
In the elderly, Cushings syndrome can exacerbate the physical and psychological changes of aging. Skin, which has already begun to thin, bruises easily and heals poorly. The risk of fractures may be compounded by osteoporosis. The mental status changes associated with Cushings syndrome may become more severe, leading to confusion, increasing dementia, paranoia, hypochondriasis, psychosis or threats of suicide. As their immune system becomes less effective due to the combined effects of aging and excessive cortisol, the elderly patient becomes more susceptible to infections, malignancies, autoimmune disorders and allergies.
Compounds acting on adrenal glands Mitotane Aminoglutethimide Metyrapone Trilostane Ketoconazole Etomidate Glucocorticoid antagonists (mifepristone) Megestrol acetate Adapted from Lancet 2001; 357: 783-91
Thomas Addison
1/100,000 people affected Affects all age groups Males and females are affected equally
Addison's sufferer John F. Kennedy. Notice the far thinner face of his brother Robert, behind him.
In 1849, Thomas Addison first described the melasma suprarenale in a paper titled A Remarkable Form of Anaemia. He chose the term anemia to reflect the chronic fatigue, muscle weakness, anorexia and weight loss that are common in Addisons disease. What were not recognized at the time were the role of the adrenal glands and the severe or total deficiency of cortisol and other adrenal hormones such as aldosterone. Today Addisons disease is best known for one of its sufferers, President John Kennedy. While it is now well-known that he had the condition, during his lifetime he went to great lengths to hide his disease.
Copyright 2011 American Society of Consultant Pharmacists
The pair of adrenal glands in the bottom are normal. Those at the top come from a patient with adrenal atrophy from with either Addison's disease or long-term corticosteroid therapy.
Primary Adrenal Insufficiency due to: Autoimmune disorders (70% of cases in US) TB (20%) most common infectious cause in the world Chronic infections HIV- most common infectious cause in US Cancer metastases Amyloidosis Surgical removal of adrenal glands Inflammation
Secondary Adrenal Insufficiency due to: Interruption of glucocorticoid medication Surgical removal of ACTH producing tumors Pituitary dysfunction
Tertiary Adrenal Insufficiency due to: Interruption of glucocorticoid medication Iatrogenic suppression of HPA axis Hypothalmic failure or dysfunction
Addisons disease affects about one in every one hundred thousand people and occurs in all age groups. It can be the result of primary adrenal insufficiency or secondary to a decline in adrenocorticotropin levels. Primary adrenal insufficiency due to autoimmune destruction of the adrenal cortex accounts for about seventy percent of Addisons cases. Tuberculosis accounts for another twenty percent. Secondary adrenal insufficiency may be due to the surgical removal of benign ACTH-producing tumors or pituitary dysfunction. Tertiary adrenal insufficiency may occur with hypothalamic failure or dysfunction. A temporary form of Addisons disease occurs when a person who has been receiving glucocorticoid medication suddenly stops or reduces the dose substantially. This may also occur in a glucocorticoid-dependent patient who become stressed and require additional increased glucocorticoids to maintain stability.
The symptoms of Addisons disease usually begin gradually. Chronic, worsening fatigue and muscle weakness, loss of appetite, and weight loss are common. Nausea, vomiting, and diarrhea occur in about fifty percent of cases. Blood pressure, which is already lower, falls further when standing, causing dizziness or fainting. Skin changes include possible hyperpigmentation covering exposed and nonexposed parts of the body. Mental status changes include irritability and depression. Patients often have a craving for salty foods.
Addisonian Crisis
Onset caused by: an illness, accident or other stressful event. Signs and Symptoms: Sudden penetrating pain in the lower back, abdomen or legs Severe vomiting and diarrhea, followed by dehydration Low blood pressure Loss of consciousness In its early stages, Addisons disease can be difficult to diagnose. A review of the patients medical history based on the symptoms may lead the clinician to suspect adrenal insufficiency, especially if there is hyperpigmentation. In about twenty-five percent of cases, however, the disease goes undetected until a stressful event such as an illness or accident causes the patient to take a dramatic downturn. This is called an Addisonian crisis or acute adrenal insufficiency, and is marked by sudden penetrating pain in the lower back, abdomen or legs, severe vomiting and diarrhea, and low blood pressure. If left untreated, an Addisonian crisis can be fatal. Therefore, it is important for patients who may be susceptible adrenal insufficiency to be aware of the signs and symptoms of adrenal crisis and to be monitored for adrenal insufficiency to prevent sudden death from Addisonian crisis.
ACTH S1mula1on Test Enzyme defect 21 Hydroxylase Direct eect increased 170HP, P decreased 11 Deoxy corGsol decreased CorGsol Secondary to HPA over ac1vity increased 4-Androstenedione
increased 4-Androstenedione
An increase in tissue corticosteroid levels during acute illness is an important protective response. Many diseases and treatments interfere with the normal response of corticosteroids to illness. This adrenal insufficiency in the critically ill is difficult to diagnose because its symptoms are usually attributed to their acute illness. Overall, the role of corticosteroids in the critically ill is controversial. There is evidence to support the use of supplemental corticosteroids in patients with established septic shock who are in an intensive care unit. It has been shown that patients with septic shock treated with hydrocortisone and fludrocortisone had a significant reduction in death from septic shock. Patients in shock may be treated with steroid replacement therapy at diagnosis and should be tested for adrenal insufficiency; treatment can then be removed if adrenal function is intact.
Resources
For additional information, see: Annane D, Sebille V, Charpentier C, et al. Effect of Treatment with Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients with Septic Shocl. JAMA, 2002; 288: 862-71. Barnette DJ. Endocrine and metabolic disorders. In: Barnette D, Bressler L, Brouse S, et al. Updates in Therapeutics: The Pharmacotherapy Preparatory Course, Vol. 2, 2008 ed. Lenexa, KS: American College of Clinical Pharmacy, 2008: 187-220. Boscaro M, Barzon L, Fallo F et al. Cushings syndrome.Lancet 2001;357:783-91 Cizza, G. & Chrousos, G. P. Adrenocorticotrophic hormone-dependent Cushings syndrome. Cancer Treatment and Research 1997;89: 25-40. Cook, D. M. & Loriaux, D. L. Cushings syndrome. Current Therapy in Endocrinology & Metabolism 1997;6: 161-164. Cooper MS and Stewart PM. Corticosteroid Insufficiency in Acutely Ill Patients. N Eng J Med 2003; 348: 727-734. Coursin DB and Wood KE. Corticosteroid Supplementation for Adrenal Insufficiency. JAMA 2002; 287: 236-40. Failor RA and Capell PT. Hyperaldosteronism and Pheochromocytoma: New Tricks and Tests. Prim Care Clin Office Pract, 2003; 30: 801-20 . Girgis R, Winter J. The effects of glucocorticoid replacement therapy on growth, bone mineral density, and bone turnover markers in children with congenital adrenal hyperplasia. J of Clin Endocrinol and Metab 1997;82:3926-3929.
Resources
Gums JG, Terpening CM. Adrenal gland disorders. In: Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM editors. Pharmacotherapy, a pathophysiologic approach, New York, McGraw-Hill Medical Publishing Division 2002, Chapter 76; 1379-1393 Lange M, Feldt-Rasmussen U, Svedsen OL, et al. High Risk of Adrenal Insufficiency in Adults Previously Treated for Idiopathic Childhood Onset Growth Hormone Deficiency. J of Clin Endocrinol Metab 2003; 88:5784-9. Mann M, Koller E, Murgo A et al. Glucocorticoidlike Activity of Megestrol: A Summary of Food and Drug Administration Experience and a Review of the Literature. Arch Intern Med 1997; 157: 1651-6. Mills JL, Schonberger LB, Wysowski DK, et al. Long-Term Mortality in the United States Cohort of Pituitary-Derived Growth Hormone Recipients. J Pediatr 2004; 144: 430-6. National Adrenal Diseases Foundation http://www.medhelp.org/nadf/: Accessed 4/29/05 National Institute of Diabetes and Digestive and Kidney Diseases: Addisons Disease http://www.niddk.nih.gov/health/ endo/pubs/addison/addison.htm: Accessed 4/29/05 National Institute of Diabetes and Digestive and Kidney Diseases: Cushings Syndrome http://www.niddk.nih.gov/ health/endo/pubs/cushings/cushings.htm: Accessed 4/29/05 Meier, C. A. & Biller, C. M. Clinical and biomedical evaluation of Cushings syndrome. Endocrinology & Metabolism Clinics of North America, 1997;26(4): 741-762.
Resources
Nieman LK. Diagnostic tests for Cushings syndrome. Ann NY Acad Sci 2002;970:112-118 Nieman, L. K. Cushings: Medical approach. Current Therapy in Endocrinology & Metabolism, 1997;6: 59-62. Orth, D. N. Cushings syndrome. N Engl J Med, 1995;332: 791-803. Parker CR. Adrenal function in aging. Current Opion in Endocrinology & Diabetes, 1999; 6(3): 210 Rocha R, Funder JW. The pathophysiology of aldosterone in the cardiovascular system. Ann NY Acad Sci 2002;970:89-100 Timiras PS. Physiological basis of aging and geriatrics. 3rd ed. Informa Health Care, 2002: 172-177. Tsigos, C. & Chrousos, G. P. Differential diagnosis and management of Cushings syndrome. Annual Review of Medicine, 1996;47: 443-461. Vaughan ED. Diseases of the adrenal gland. Med Clin N Am, 2004; 88:443-66
Pagets Disease
Learning Objectives
By the end of this Review Concept you should be able to: Identify the common clinical manifestations and complications associated with Pagets disease. Compare and contrast the pharmacological and non-pharmacological therapies used to treat Pagets disease Prepare a treatment plan for an elderly patient with Pagets disease given a patient case.
Initial Phase: intense osteoclastic activity and bone resorption. Mixed Phase (Osteolytic-Osteoblastic Phase): active bone resorption & formation of woven bone with ineffective mineralization. Late Sclerotic Phase: Dense cortical and trabecular bone deposition dominates resulting in weak, chaotic bone that also encroaches on marrow. Bones Commonly Aected Bones Pelvis Lumbar spine Femur Thoracic spine Skull Tibia Humerus Cervical spine Percentage 72 58 55 45 42 35 31 14 In normal bone, the process of remodeling is coupled so that bone resorption occurs at a similar rate to bone formation. The cells responsible for these actions are osteoclasts and osteoblasts, respectively. When this process becomes uncoupled, as in osteoporosis or Pagets disease, greater resorption occurs resulting in loss of bone mineral density. Pagets disease is characterized by intense localized osteoclastic and osteoblastic activity that progresses in three general phases. In the initial phase, there is a localized increase in bone resorption. Numerous osteoblasts overlie previously resorbed bone surfaces and result in increased bone formation. During the mixed phase, in-growth of highly vascularized fibrous tissue occurs. In the sclerotic phase, dense cortical and trabecular bone encroach on the marrow space. Pagets disease can affect any bone although the most commonly affected bones are those of the axial skeleton, long bones and pelvis. In the majority of patients, Pagets disease affects at least two bones; however, up to onethird of patients will only have one bone that is involved.
Information from Ooi CG, Fraser WD. Pagets disease of bone. Postgrad Med J 1997;73:70
Slow-virus infection Genetics (associated with chromosome 18q) Hormonal imbalance Environmental factors, such as dietary calcium intake and exposure to industrial toxins The exact cause of Pagets disease still is unknown. Possible causes include a slow virus infection, as evidence of previous infection with measles or respiratory syncytial viruses are often found in Pagets patients. Other theories implicate hormonal imbalances such as hyperparathyroidism, excess growth hormone secretion, adrenal insufficiency and calcitonin deficiency. Additionally, genetics may also play a role in the etiology of Pagets disease as fifteen to forty percent of patients have a positive family history of the disease and at least one first-degree relative with the disorder. Increasingly, there is more information on genetic abnormalities believed to be involved in the pathogenesis of Pagets. Identification of the genes involved in osteoclastogenesis are mutated in Pagets. This mutation combined with nongenetic factors, like infection or environmental exposure, form the leading theory on how Pagets disease occurs. From a clinical standpoint, this new information leads to the question of whether treatment should be started in patients carrying the Pagets-causing genetic mutations.
http://eduserv.hscer.washington.edu/ hubio553/totrad/SCAR/commonmsk.html
From: http://www.surgeongeneral.gov/library/bonehealth/chapter_3.html
Anterior and posterior whole body images from a radionuclide bone scan. Multiple bones (skull, sternum, humerus, right hemipelvis, and left tibia demonstrate intense uptake, consistent with Paget's disease. Up to 25 % of Paget's patients have no bone pain at the time of diagnosis. Therefore, it is not unusual to first diagnose Paget's disease on images performed for some other completely unrelated reason.
Neurological: Deafness Headache Spinal cord compression Brain stem compression Trigeminal neuralgia Heart failure Kidney stones
Malignant bone tumors are one of the most serious complications of Pagets Disease. Fortunately this is relatively rare, occurring in about 0.7% to 0.9% of patients with Pagets disease. Osteosarcomas, chondrosarcomas, and fibrosarcomas may develop in a preexisting pagetic lesion, often obscuring the ability to detect the malignancy early. Increased bone pain or deformity should be followed up by radiologic evaluation, and if necessary, by bone biopsy. Because of this increased risk of osteosarcoma, patients with Pagets should not be treated with terparatide, according to the products black box warning. Another serious complication of Pagets disease is fractures. These can result in further complications such as reduced mobility, functioning and additional decompensation. If spinal cord compression is involved the patient may also become paraplegic.
Lab Evaluation
Radiologic diagnosis Severe localized osteolysis Osteosclerotic lesions Widespread osteosclerosis Radiologic tests Bone scintigraphy (Gallium 67) MRI Bone biopsy Biochemical bone markers: Serum markers of bone turnover Serum alkaline phosphatase Serum bone-specific alkaline phosphatase Tartrated-resistant acid phosphatase Procollagen type I N-terminal peptides (PINP) Serum bone sialoprotein Serum osteocalcin B-carboxyterminal telopeptide of type-I collagen (SCTX)
Urine markers of bone turnover Pyridinoline (PYD) Hydroxyproline (Hyp) Amino (NTX) & ?-carboxyterminal (CTX) of collagen type I Deoxypyridinoline (DPD) Urinary calcium Markers of bone formation Bone-specific alkaline phosphatase N-terminal and C-terminal extension peptides of procollagen
Lab Evaluation
As mentioned earlier, most patients are diagnosed incidental to radiographs or a routine laboratory work-up. A conventional bone scan is recommended before and six months after treatment, and every 12 months thereafter depending on the behavior of the Pagetic lesion. Radiographs should be obtained before treatment and every one to two years thereafter to monitor changes in modeling and remodeling. Radionucleotides such as Gallium 67 can help localize Pagetic lesions and may be used to follow the response to drug therapy. Such bone scans should be done on every patient suspected to have Pagets because they will identify fifteen to thirty percent of lesions not picked up on xrays. Although rarely done, a bone biopsy is used to evaluate malignancy when MRI indicates mixed osteoblastic and osteolytic vertebral lesions. Three decades ago it became possible to measure the rate of bone resorption by using urinary hydroxyproline, as well as the rate of bone formation, indicated by plasma alkaline phosphatase. Both are increased considerably by the excess bone turnover of pagetic bone. Since that time there has been an explosion of biochemical bone markers. Historically, the two most important markers in Pagets disease are total serum alkaline phosphatase and urinary pyridinoline. However, it is now appreciated that hydroxyproline, because of extensive breakdown before excretion, does not reflect collagen turnover accurately. Newer assays of nonmetabolized collagen peptides, including Ntelopeptides and pyridinoline crosslink assays, are more sensitive markers of bone resorption and are readily available through commercial laboratories. Serum markers of bone turnover show lower biological variability than urinary markers and are therefore more sensitive indices of the activity of the disease. Serum alkaline phosphatase can be considered to be a sensitive and inexpensive marker for therapeutic monitoring of Pagets disease. Patients should be followed by measuring bone markers every three to six months depending on the activity of the Pagetic lesion and the drug used. Treatment should be recommended when remodeling indices rise above the upper limits of normal or by 25% above the previous lowest point.
Both symptomatic and asymptomatic patients with increased parameters of bone remodeling are candidates for drug therapy, especially if the alkaline phosphatase level is at least 25% above the baseline level. Bone pain can increase the need for specific drug treatment, especially if it is unrelieved by nonsteroidal anti-inflammatory drugs or acetaminophen. Preparation for orthopedic surgery, and medication complications such as hypercalcemia, hearing loss, and spinal cord or nerve dysfunction are also good indicators for drug therapy. Drug therapy may be recommended to prevent fractures or skeletal deformity in patients with active Pagets disease. Because Pagets disease is a chronic disease the goal of therapy is to palliate bone pain and to prevent the progression of the disease.
Pagets disease is a chronic, progressive disease with the potential for severe complications and significant reduction in quality of life. Therefore even asymptomatic patients are considered for treatment if they show active disease as indicated by abnormal biochemical markers. However, there is no conclusive evidence to suggest that complications can be prevented by controlling bone remodeling through drug therapy. Several agents are helpful in treating Pagets disease and are discussed below Bisphosphonates are the treatment of choice because they bind to the surface of hydroxyapatite crystals, decreasing bone resorption and disrupting osteoclasts and cellular activity. The main action of bisphosphonates is to induce marked and prolonged inhibition of bone resorption by decreasing osteoclastic activity. Disease activity stays low for months or years after cessation of these medications. Bisphosphonates can cause a 70 percent decrease in biochemical markers in one half of patients. As newer more potent Bisphosphonates are developed the reduction in biochemical markers will likely increase. Bisphosphonates also may demonstrate some analgesic effect for bone pain. Bisphosphonates appear to be more effective than calcitonin in suppressing the histological and biochemical activity in Pagets disease. Calcitonin is no longer considered to be the treatment of choice for Pagets disease. Calcitonin is a product of the thyroid C-cells and its action in the body is to decrease osteoclastic bone resorption. Calcitonin is appropriate for patients who show no response to the bisphosphonates or when used for a few weeks to decrease bone pain. Analgesics such as acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) may be useful in symptomatic patients to reduce bone pain.
1st Generation Etidronate (Didronel) Dosing: 5 mg/kg body weight po qd for six months Side effects: Defective mineralization of newly formed bone matrix Increased risk of fracture
Watch for: Low blood calcium Esophagitis GI distress Diarrhea Cramps Headache Bone pain Monitor: Response to drug Resolution of symptoms Alkaline phosphatase and either free pyridinoline cross-links or telopeptides
One common side effect of bisphosphonates is low blood calcium. Therefore, patients must have adequate intake of Vitamin D and oral calcium. T The oral aminobisphosphonates such as pamidronate and alendronate as well as risedronate can all cause heartburn, esophageal irritation, esophagitis, abdominal pain, diarrhea and other adverse gastrointestinal effects. Gastrointestinal distress appears to be lessened with third generation agents. To avoid severe esophageal irritation, the tablets must not be chewed or allowed to dissolve in the mouth, and must be taken with eight ounces of plain water while in an upright position. For 30 minutes after taking the drug, the patient must not eat or drink anything other than water and must avoid lying down. Food and vitamin supplements must be withheld for at least two hours after administration. Pagets patients taking bisphosphonates should be monitored for changes in bone resorption indices as well as serum calcium levels. Lab tests for alkaline phosphatase and either free pyridinoline cross-links or telopeptides can help verify if the patient is responding to treatment.
Although calcitonin is no longer considered the treatment of choice for Pagets disease, there is still a role for its use. Calcitonin can be used to reduce bone pain associate with pagetic lesions, fractures or the initiation of bisphosphonate therapy. Long-term therapy is limited by the development of resistance. Over treatment periods of two to three years, one quarter of patients acquire a resistance to calcitonin due to an increased level of neutralizing antibodies and/or by receptor down regulation. Calcitonin is available in an injectable salmon and human forms and as a nasal spray in salmon form only. With intranasal delivery of calcitonin, there is lower bioavailability; hence the dosage is higher. Salmon calcitonin may be problematic over human calcitonin due to the production of antibodies that attenuate the effectiveness of the agent in one to two thirds of patients. Those that either do not respond to salmon calcitonin or develop a resistance to it should try the human form.
Side effects are seen in twenty percent of patients. Common symptoms include nausea, vomiting and facial flushing. Rhinitis is experienced in patients with nasal administration.
Orthopedic intervention may be required due to skeletal complications seen with Pagets disease. Bowing of the femur and tibia, and delayed fractures are examples of such complications. Complications of elective surgery could bring the risk of infection, hemorrhage and loosening of the prosthetic joint replacement. Calcitonin and bisphosphonates may postpone need for surgery, however, surgery can help improve mobility and decrease the bone pain.
Resources
For additional information, see: Ankrom MA, Shapiro JR.Pagets disease of bone (osteitis deformans).J Am Geriatr Soc 1998;46:1025-33. Buckler H, Fraser W, Hosking D, et al. Single Infusion of Zoledronate in Pagets Disease of Cone: A PlaceboControlled, Dose-Ranging Study. Bone, 1999; 24; 81S-5S. Cacace E. Ruggiero V. Matulli C. Uras L. Perpignano G. Markers of bone resorption in bisphosphonate therapy of Paget's disease. Clinical & Experimental Rheumatology. 22(4):502, 2004 Coppes-Zantinga AR, Coppes MJ.Sir James Paget (1814-1889): a great academic victorian. J Am Coll Surg 2000;191 (1):70-4. Delmas PD, Meunier PJ.The management of Pagets disease of bone. N Engl J Med 1997;336(8):558-66. Grauer A, Heichel S, Knaus J, et al. Ibandronate treatment in Pagets disease of the bone. Bone. 1999;24(5 Suppl): 87S-89S. Hadjipavlou AG, Gaitanis IN, Kontakis GM. Pagets disease of the bone and its management. J Bone Joint Surg Br 2002;84-B(2):160-9. Hamdy RC. Pagets disease of the bone. Clin Geriatr Med 1994;10(4):719-35.
Resources
Holgado S, Rotes D, Guma M, et al. Pagets Disease of Bone in Early Life. Ann Rheum Dis, 2005; 64: 306-8. Hosking D, Meunier PJ, Ringe JD et al.Pagets disease of bone: diagnosis and management.BMJ 1996;312(7029): 491-4. Kanis JA, McCloskey EV, Beneton MN. Clodronate and osteoporosis. Maturity 1996; 23 Suppl:81-6. Kurzl RG.Pagets disease. Sem Dermatol 1996;15(1):60-6. Langston AL. Ralston SH. Management of Paget's disease of bone. Rheumatology. 43(8):955-9, 2004 Lyles KW. What is "resistance" in Paget's disease of bone? Arthritis & Rheumatism. 48(8):2097-9, 2003 Miller PD, Brown JP, Siris ES et al. A randomized, double-blind comparison of risedronate and etidronate in the treatment of Pagets disease of bone. Am J Med 1999;106:513-20. Mirra JM, Brien EW, Tehranzadeh J. Pagets disease of bone: review with emphasis on radiologic features, Part II.Skeletal Radiol 1995;24(3):173-84. Onishi Y, Ohara K. Ectopic extramammary Pagets disease affecting the upper abdomen. Br J Dermatol 1996;134(5): 958-61. Paget Foundation, http://www.paget.org/
Resources
Pearce JMS.Sir James Paget: a biographical note.Q J Med 1997;90:235-7. Product Information: Forteo(TM), teriparatide (rDNA origin) injection. Eli Lilly & Co., Indianapolis, IN (PI revised 2/2004) reviewed 12/2004. Redina D, Mossetti G, Viceconti, et al. Risedronate and Pamidronate Treatment in the Clinical Management of Patients with Severe Pagets Disease of Bone and Acquired Resistance to Bisphosphonates. Calcif Tissue Int, 2004; 75: 189-96. Reid IR, Miller P, Lyles K, et al. Comparison of single infusion of zoledronic acid with risedronate for Pagets disease. N Engl J Med 2005;353:898-908. Roodman GD and Windle JJ. Paget Disease of Bone. J Clin Invest, 2005; 115: 200-8. Schneider D, Hofmann MT, Peterson JA. Diagnosis and treatment of Pagets disease of bone.Am Fam Physician 2002;65(10):2069-72. Takata S, Yasui N, Nakatsuka K, et al. Evolution of Understanding of Genetics of Pagets Disease of Bone and Related Disease. J Bone Miner Metab, 2004; 22: 519-23. Woitge HW, Oberwittler H, Heichel S, et al. Short and long term effects of ibandronate treatment on bone turnover in Paget disease of the bone. Clin Chem. 2000;46(5):684-90.
Learning Objectives
By the end of this Review Concept you should be able to: Identify a patient experiencing menopausal symptoms, and the signs which would coincide with a diagnosis of menopause. Compare and contrast the treatment of the signs and symptoms of menopause historically with how it is treated today. Educate a menopausal female on the risks and benefits of certain non-pharmacological and pharmacological therapies for the treatment of symptoms of menopause. Suggest a treatment plan for a menopausal female experiencing distressing symptoms of menopause.
Introduction to Menopause
Perimenopause: Time between menstrual irregularity and menopause Natural Menopause: No spontaneous menstrual period (amenorrhea) for 12 consecutive months with no other pathologic or physiologic cause Age of onset is between 40 60 years Associated with somatic, physiological, and psychological changes Premature Menopause: Onset prior to age 40 years Caused by genetics, viral infection, smoking Induced Menopause: Cessation of menses following hysterectomy with or without bilateral oophorectomy Iatrogenic ablation of ovarian function (ie. chemotherapy, radiation)
Introduction to Menopause
Menopause is a significant life event for women and can be associated with somatic, physiological, and psychological changes. Since healthy women spend about one-half to one-third of their lives in the menopausal state, it is important for providers caring for aging female patients to have a good overall understanding of the issues surrounding menopause. Perimenopause is generally defined as the time between menstrual irregularity and menopause. Women experience either a change in menstrual cycle length or skipped menstrual periods. In addition, many women experience similar symptoms as women who are postmenopausal. It is not until a woman experiences no menstrual period for twelve consecutive months that she is considered postmenopausal. The hallmark of menopause is the major change in estrogen production and metabolism, which causes characteristic symptoms including vasomotor symptoms such as hot flashes and night sweats and genitourinary changes such as vaginal dryness and dyspareunia or painful intercourse. These symptoms may be disabling for some but not all women. Menopause generally occurs between the age of forty to sixty and the median age of onset is between fifty and fifty-two years of age. Premature menopause can be defined as ovarian failure and menstrual cessation prior to the age of 40. Genetic predisposition, viral infection, and smoking can increase the risk for premature menopause. In some instances, menopause may be surgically induced following surgical removal of both ovaries or as a consequence of chemotherapy or radiation.
Estrogen Promote development of female secondary sex characteristics Regulation of the menstrual cycle 3 types exist in significant quantity: 17-estradiol Estrone Estriol Progesterone Regulation of the menstrual cycle, pregnancy, and embryogenesis Testosterone Precursor to estrogen synthesis Promotes sexual functioning Estrogen, progesterone, and testosterone are endogenous steroids which are synthesized in the ovaries mainly from cholesterol. Progesterone and testosterone are synthesized first during the follicular phase of the ovarian cycle. Before these initial two hormones can leave the ovaries, almost all the testosterone and much of the progesterone are converted into estrogens by the granulosa cells. The liver conjugates the estrogens to form glucuronides and sulfates. About one-fifth of these conjugated products are excreted in the bile while the remainder is excreted in the urine. The liver converts the potent estrogens, 17estradiol (most abundant) and estrone, into the almost totally impotent estrogen estriol. Thus, diminished liver function actually increases the amount of activity of estrogens in the body.
Within a few minutes after secretion, almost all the progesterone is degraded to other steroids that have no progesteronic effect. Again, the liver is vital for the metabolic degradation of progesterone. Differences exist in hormone release in women during pregnancy. Estrogens are secreted in major quantities primarily by the ovaries in non-pregnant women, while during pregnancy estrogens are secreted from the placenta. In non-pregnant women, progesterone is secreted in significant amounts only during the latter half of each ovarian cycle by the corpus luteum. During pregnancy, especially after the fourth month of gestation, the placenta secretes large amounts of progesterone.
Along with endocrine changes, somatic and physiological changes are noted in women experiencing menopause. To begin with, the ovaries shrink and have a wrinkled appearance. The endometrium thins and may become atrophic, resulting in cystic hyperplasia in up to 20% of cases. Mild hair growth is observed, as well as other androgenic effects such as a deeper voice, acne, increased weight, and sweating and breasts become smaller in size.
Vasomotor Symptoms: Experienced by 75 85% of menopausal women Most common 12 24 months after the last menstrual period Symptoms: hot flashes, night sweats Felt in face, neck, and upper trunk Lasts from 30 seconds to several minutes Frequency and severity can vary based on: Race/ethnicity Menstrual status (perimenopausal versus postmenopausal) Body mass index (BMI) Physical activity Smoking status GU Complaints: Fluctuating hormone levels resulting in irregular uterine bleeding and eventual amenorrhea (no menstrual period) Atrophy of urogenital epithelium Vulvovaginal atrophy resulting in vaginal dryness, dyspareunia (painful intercourse) and increased UTIs Loss of uterine support resulting in incontinence
Loss of estrogen in postmenopausal women can increase the risk of osteoporotic fractures due to an increased bone resorption. Additionally, low estrogen concentrations can lead to lipid alterations such as an increase in LDL and a decrease in HDL which can increase risk of cardiovascular problems such as coronary artery disease. In fact, menopause increases a womans risk of atherosclerosis to that of a male in the same age group. Increases in fibrinogen and thromboxane, and decreases in PGI2 and nitric oxide may increase vascular stiffness. Fatigue and mood changes such as depression, along with the physiological changes to the genitourinary tract can cause sexual dysfunction in postmenopausal women leading to further psychological distress. Other potential psychological symptoms include problems with memory, insomnia, anxiety, and irritability.
Essentials of Diagnosis
Irregular menstrual cycles followed by 1 year of amenorrhea Additional findings: FSH >30mIU/mL Hot flashes/flushes and night sweats Decreased vaginal lubrication Thinned vaginal mucosa (with or without dyspareunia)
Menstrual irregularity preceding cessation of menses for 12 consecutive months is the hallmark feature for menopause diagnosis. In most cases, patients reports of amenorrhea and symptoms commonly associated with menopause are sufficient for a clinical diagnosis. In some cases, a serum FSH level may be ordered. A rise in serum FSH concentrations, greater than 30mIU/mL, is indicative of menopause. Although LH concentrations also rise in menopause, it is not routinely measured to aid in diagnosis. A Pap smear and pelvic exam can aid in assessing physiologic changes that occur during menopause.
Early observational studies have shown a 30% to 50% reduction in CHD and total mortality in postmenopausal women using estrogen. Therefore, all women entering menopause received long-term hormone therapy (HT), previously known as hormone replacement therapy (HRT). The hormone that was in greatest need of replacing, particularly in the elderly, was estrogen. Women with an intact uterus were also prescribed concomitant progesterone to minimize risk for endometrial cancer. In some cases, women were also supplemented with androgens for menopause-related symptoms such as decreased libido. Although used primarily for management of vasomotor symptoms, HT was marketed to help women maintain their youth and beauty, as well as prevent chronic diseases such as coronary heart disease (CHD), osteoporosis, and Alzheimers disease.
More recently, randomized clinical trials were launched to test the hypothesis of estrogens potential for cardiovascular prevention. Results of primary and secondary prevention trials such as the Heart and Estrogen/Progestin Replacement Studies (HERS & HERS II) and the Womens Health Initiative (WHI) now show that estrogen-based therapy may actually increase cardiovascular and other risks.
Heart and Estrogen/Progestin Replacement Study and Follow-up (HERS and HERS II)
Randomized, double-blinded, placebo-controlled trial to determine the effects of estrogen plus progestin compared with placebo in older postmenopausal women with coronary heart disease (CHD) 2,763 women, average age of 67 with average of 6.8 years of observation (HERS + HERS II) Women received 0.625 mg conjugated estrogens and 2.5 mg medroxyprogesterone or placebo Results: Increased rates of venous thromboembolism and biliary tract surgery in older women with CHD on HT No overall effect of HT on cardiovascular disease (CVD) event rates The Heart and Estrogen/Progestin Replacement Studies, known as the HERS trials were the first randomized, controlled trials in older postmenopausal women with coronary heart disease (CHD) designed to examine the effect of long-term postmenopausal hormone therapy on both cardiovascular and non-cardiovascular disease outcomes. The HERS trial assessed the efficacy of HT for secondary prevention of CHD. Over the 4.1 years of follow-up for the HERS trial there were no overall differences in CHD endpoints between women randomized to placebo or HT. However, there was a trend toward decreasing risk of CHD with increasing duration of HT use. This was believed to result from the increased early thrombotic effects of estrogen during the first years of the trial. Since these results contradicted data from observational studies, many clinicians concluded that a net benefit for HT would have been observed with longer duration of use. The HERS II trial was a continuation of the original HERS trial with follow-up for an additional 2.7 years in order to allow for longer duration of HT exposure. Surprisingly, the lower rates of CHD events among women in the hormone group in the final years of the first HERS trial did not persist during additional years of follow-up in HERS II. After 6.8 years, HT did not reduce the risk of cardiovascular events in women with CHD. Furthermore, estrogen plus progestin in older women did not produce favorable trends in overall rates of cardiovascular disease, fracture, or death. The lack of benefit of HT in high-risk women has been confirmed in additional trials. HERS II also failed to show any benefit in preventing ischemic stroke. Non-cardiovascular end points such as overall risk of venous thromboembolism and biliary tract surgery were also significantly higher in HT patients.
Copyright 2011 American Society of Consultant Pharmacists
The WHI was a 15 year project sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and National Institutes of Health (NIH) to address common causes of death, disability, and quality of life in postmenopausal women. Launched in 1991, the trial recruited 161,808 postmenopausal women. Women could be enrolled in any or all of the clinical trials including HT, dietary modification, and calcium/vitamin D. In addition, the WHI included an observational study. The HT trial of the WHI is the largest, randomized, primary prevention trial to assess the safety and efficacy of estrogen plus progestin and estrogen alone in reducing risk of cardiovascular disease (CVD), breast and colorectal cancers, and osteoporotic fractures. The HT trial involved 27,348 participants ranging from 50-79 year of age.
Copyright 2011 American Society of Consultant Pharmacists
The estrogen alone arm of the HT trials was a parallel clinical trial to the estrogen plus progestin arm but was conducted in women who had a hysterectomy. 5,310 women who had a hysterectomy were randomized to 0.625 mg/d of conjugated estrogen and 5,429 women received placebo. The primary outcome was CHD incidence, both nonfatal myocardial infarction or CHD death. Invasive breast cancer incidence was the primary safety outcome.
Copyright 2011 American Society of Consultant Pharmacists
NEJM. 2003;349(6):523-534 (Figure 2). Copyright 2011 American Society of Consultant Pharmacists Arch Intern Med. 2006;166:357-365.
JAMA. 2003;289(20):2673-2684.
The breast cancer results of the WHI were surprising based on the different effects observed with estrogen plus progestin versus estrogen alone. For women taking estrogen plus progestin, there was a significant 24% increase in incidence of total and invasive breast cancers. HT use less than 5 years did not seem to have a major impact on breast cancer risk. Incident breast cancers diagnosed among combined HT users were similar in histology and grade, but larger and at more advanced stage compared to those diagnosed in the placebo group. In contrast, estrogen alone therapy was associated with a nonsignificant 20% decrease in invasive breast cancer. For incident invasive breast cancer cases, no difference in cancer stage or tumor grade was noted. Differences in findings between estrogen plus progestin and estrogen alone on breast cancer risk may be related to differences in uterine status and baseline characteristics among the study populations. Despite differences in breast cancer incidence, use of both HT regimens was associated with a substantial increase in the number of abnormal mammograms.
Endometrial cancer incidence is significantly increased with unopposed estrogen use in women with a uterus. Addition of progestin to the regimen decreases this risk in women with an intact uterus. In the combined HT arm of the WHI, a nonsignificant decrease in endometrial cancer was noted. For cases of endometrial cancer that occurred, no difference was seen in tumor histology, stage, or grade. Conflicting data exists regarding risk for colorectal cancer among users of estrogen plus progestin and estrogen alone. A significant decrease in colorectal cancer incidence was reported early after initiation of estrogen plus progestin whereas a nonsignificant increase was reported among estrogen alone users.
Observational and randomized controlled trials have shown that postmenopausal women who use hormone therapy are at increased risk for VTE. The risk emerges 1 to 2 years after initiation of therapy and decreases over time. Although still at risk, hormone therapy users less than 60 years of age are at lower risk for VTE. Women with a prior history of VTE or women who possess factor V Leiden are at increased risk for VTE with HT use.
For years basic research into estrogens effects on the brain have provided tantalizing evidence of how beneficial estrogen is to the brain of women. In postmenopausal women, the effect of reduced sex hormones, especially estrogen and progesterone, on cognitive decline is of particular interest because of their modulating effects on neurotransmitters, neuroconnectivity, and neuroprotection. In fact, estrogen receptors are widely distributed throughout the brain..
Many retrospective and cohort studies have shown an association between either no HT and worsening cognitive function with age, or HT and improved cognitive function with age. However, much like the recent findings of the HERS trials and the WHI on the negative consequences of HT, recent clinical trials of HT for improving cognition have also proved disappointing. One large study of 120 mildly-to-moderately demented women treated with either conventional doses of CEE 0.625 mg/d or higher doses of 1.25 mg/d CEE versus placebo showed no improvement after one year of treatment. The results of the Womens Health Initiative Memory Study (WHIMS), which is a substudy of the WHI, now complete the picture of estrogen when used for primary prevention of cognitive decline. Although the number of women with dementia was small, the data presented suggest an increased risk for all types of dementia due to HT. Overall, the WHIMS revealed that hormone therapy increased the risk of dementia. The reported increased risk of probable dementia would lead to an additional 23 cases of dementia per 10,000 women per year for both HT arms. The risk of being diagnosed with mild cognitive impairment, was increased by 37% for women taking estrogen plus progestin and 34% for women taking estrogen alone compared with placebo. Data analysis in both HT arms show that these rates began to separate in the first year. Some of this increased risk of developing dementia may be related to the increase in vascular dementia secondary to the increase in ischemic strokes seen in the WHI. Regardless of the cause, there is little evidence to suggest that HT can prevent or improve dementia or Alzheimers disease.
The results of the WHI did provide some good news in that the results are consistent with the observational data and limited data from clinical trials that estrogen is able to maintain bone mineral density. In fact, estrogen can prevent hip, vertebral and other osteoporotic fractures. While that may not sound surprising, it should be when you consider that the WHI is the first trial with definitive data supporting the ability of postmenopausal hormone to prevent fractures at the hip, vertebrae, and other sites.
All analyses for the WHI Quality of Life study focused on changes in health-related quality of life from baseline to 1 year in relation to study-group assignment. It has been postulated that the positive effects of estrogen plus progestin on health-related quality of life may be masked or delayed during the first year, when some women have bothersome side effects such as bleeding and breast pain. The WHI results showed no evidence that long-term use (over 3 years) of estrogen plus progestin has a more positive effect on health-related quality of life than short-term use. Sleep disturbance is a common and distressing symptom in postmenopausal women that may be slightly alleviated with the use of estrogen plus progestin.
As a result of the recently published findings of the WHI and other trials, the FDA has required new black box warnings be added to estrogen-containing products. The warning includes: (1) Estrogens increase the chances of getting cancer of the uterus; (2) Do not use estrogens with or without progestins to prevent heart disease, heart attacks, or strokes; and, (3) Using estrogens with or without progestins may increase a womans chances of getting heart attacks, strokes, breast cancer, and blood clots. A woman and her healthcare provider should talk regularly about whether she still needs treatment with estrogens.
Assessment of symptoms and their impact on quality of life are a key component of the menstrual evaluation. It is important to elicit information regarding the patients most bothersome symptoms to determine their desire for treatment and how to appropriately manage these specific symptoms. The risks and benefits of the available treatment options should be weighed, keeping in mind patient specific factors such as past medical history, family history, social history, and current medication use. In addition, other factors affecting postmenopausal health such as bone density; vaginal, bladder, and sexual function; cardiovascular health; thromboembolic risk; and cancer risk should be included in the assessment. For most women early in their postmenopausal years, which is considered less than 5 years since menopause, HT remains the gold standard for management of vasomotor symptoms according to the American Association of Clinical Endocrinologists and North American Menopause Society. For patients unable or unwilling to take HT, several nonhormonal agents may be considered.
Copyright 2011 American Society of Consultant Pharmacists
Estrogens
FDA Approved Indications: Treatment of moderate to severe vasomotor symptoms associated with menopause Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause Prevention of postmenopausal osteoporosis Use: Gold standard for management of vasomotor symptoms related to menopuse Administered continuously Combined with a progestin depending on whether the woman has an intact uterus Effect: Effect of estrogen on hot flashes and sleep
Estrogens
Side Effects: Breast tenderness, bloating, and nausea Migraine headaches Cholecystitis Endometrial cancer Breast cancer Stroke PE DVT Oral
Estrogen
Products
Prepara1ons
Conjugated
Equine
Estrogen
(CEE)
SyntheGc
Conjugated
Estrogens
(plant-derived)
Esteried
Estrogens
Micronized
17
Estradiol
Estropipate
Premarin
CenesGn,
Enjuvia
Estratab,
Menest
Estrace,
Gynodiol
Ogen,
Ortho-Est
Brands
()
Dose
0.31.25
mg/day
0.31.25
mg/day
0.31.25
mg/day
0.52.0
mg/day
0.756
mg/day
Estrogens
Transdermal
Estrogen
Products
Prepara1ons
Transdermal
17
Estradiol
Estradiol
Gel
Estradiol
Transdermal
Spray
Brands
()
Dose
Alora, Climara, Esclim, 0.0250.1 mg patch 2x/wk Estraderm, Vivelle, Vivelle-Dot 14 mcg patch every week Menostar EstroGel, Elestrin Evamist Apply 1.25 g /day 1-3 sprays/day
Vaginal Estrogen Products Prepara1ons Conjugated Equine Estrogen Brands () Premarin Dose 0.5-2 g intravaginally daily (3 wks on and 1 wk o) 2-4gm intravaginally daily for 2 wks, then dose daily for 2 wks, then 1gm dose 1-3x/wk 1 ring every 3 months (0.0075 mg) 1 ring every 3 months (0.5-1 mg) 1 vaginal tablet (25 mcg) 2x/wk
Micronized 17 Estradiol
Estrace
Estring Femring
Vagifem Estradiol Vaginal Tablet Copyright 2011 American Society of Consultant Pharmacists
Estrogens
Recommendations: Lower doses of systemic estrogen is preferred for management of vasomotor symptoms 0.3 mg conjugated equine estrogen daily 0.25-0.5 mg oral micronized 17 estradiol daily 0.025 mg transdermal 17 estradiol Local estrogen therapy is preferred for patients who only complain of vaginal symptoms Estrogen therapy is FDA approved to manage symptoms related to menopause. Estrogen is 80-90% effective in managing moderate to severe vasomotor symptoms. In addition, estrogen is effective in treating moderate to severe vulvar and vaginal atrophy associated with menopause. However, when used solely for treatment of vaginal symptoms, vaginal creams, gels, rings or tablets are preferred. In women with a uterus, estrogen therapy should be given in combination with a progestin to minimize risk for endometrial cancer. Although estrogen is also approved for prevention of postmenopausal osteoporosis, it should not be used solely for this reason. Side effects of estrogen therapy include those associated with menstrual cycles such as breast tenderness, bloating, and some nausea. The use of estrogen has also been associated with an increase in cholecystitis. For those women who are prone to migraine headaches, estrogen may increase their frequency. Endometrial cancer has a wellrecognized association with hormone therapy. In women receiving both estrogen and progestin the risk of breast cancer was increased but not until 5 years in the WHI trial suggesting that longer duration of use increases the risk.
Estrogens
Estrogens come in many preparations, such as oral, transdermal, intravaginal,and intramuscular forms as well as estrogen-based vaginal rings, creams, and intramuscular shots. Regardless of the estrogen product used, the American College of Obstetrics and Gynecology (ACOG) and the North American Menopause Society (NAMS) recommend use of estrogen products only for the management of vasomotor symptoms related to menopause. Dosage requirements, as always, will depend on the individual and it is best to start with the lowest dose and titrate at a minimum of at least 4 to 8 weeks. Lower estrogen doses have demonstrated nearly equivalent vasomotor symptom relief. Risks and benefits to each individual patient should also be taken into account. Based on available data regarding emergence of cardiovascular and breast cancer risks, HT should not be used beyond 5 years. In addition, it is recommended that women be monitored every 6 to 12 months to assess continued need for HT. Estrogens are metabolized to inactive compounds in the liver (sulfates and glucuronides) and excreted in the urine and bile. Some reabsorption takes place from the intestine with return to the liver via the portal venous system. Esterified estrogens are rapidly metabolized in the liver and gastrointestinal tract and then excreted in the urine and bile. Estradiol is rapidly metabolized in the liver to the less active estriol and estrone. Oral estradiol undergoes extensive first-pass metabolism. Estradiol is excreted in the urine as the sulfate and glucuronide esters along with a small amount of unchanged drug. Estriol undergoes rapid glucuronide conjugation after oral doses, with only 1 to 2% appearing in the circulation as unchanged compound. There is no conversion of estriol to estradiol in vivo. Estrone is rapidly metabolized in the liver and undergoes extensive first- pass metabolism to less active products such as estriol. Estropipate is rapidly metabolized and undergoes extensive first-pass metabolism; as a derivative of estrone, the drug is first metabolized to the less potent estrogen, estriol. Topical and transdermal estrogen preparations have the advantage of bypassing firstpass metabolism so lower doses are needed compared to oral estrogens. In addition, they do not increase triglycerides. In the absence of head-to-head randomized controlled trials, data regarding differences between types and formulations of estrogen are assumed to be the same. There is some evidence that transdermal 17 estradiol may be associated with lower risk of deep venous thrombosis than oral estrogen, however, more research in this area will need to be conducted.
Copyright 2011 American Society of Consultant Pharmacists
Progestins
Use: Decrease risk of endometrial cancer and hyperplasia Decrease risk of estrogen-induced irregular bleeding May help in the prevention of osteoporosis Administered cyclically or continuously Side Effects: Menstrual symptoms Limited bleeding Weight gain Headache Drowsiness Altered cholesterol levels Decreased HDL Increased LDL
Preparations:
Prepara1on
Brand(s)
Dose 510 mg/day for 5-10 days 200 mg/day on days 1-12 2.510 mg on days 112 20 mg twice daily
Medroxyprogesterone acetate Provera Micronized progesterone Norethindrone acetate Megestrol acetate Prometrium AygesGn Megace
Progestins
The primary menopause-related indication for progestin use is endometrial protection from unopposed estrogen in women with an intact uterus. Progestin is generally not indicated when low-dose estrogen is administered locally for vaginal atrophy. In addition, progestin can also decrease the risk of estrogen-induced irregular bleeding. However, it is controversial whether progestin reduces or enhances estrogens effect on breast cancer or if it can prevent osteoporosis. Although progestin may be given cyclically or continuously, intermittent dosing may be preferred to minimize overall hormone exposure. The dose and duration of use affect its ability to prevent endometrial hyperplasia. Bleeding may occur, but will be limited if therapy is continued on a daily basis. As with estrogen, the side effects of progestin include symptoms associated with the menstrual cycle such as: breast tenderness, bloating, edema, anxiety, and depression. Progestins produce a dose-related increase in blood pressure by causing sodium and water retention. Weight gain, headaches, and drowsiness are also common side effects. Progestin appears to have an impact on lipid parameters, decreasing HDL levels and increasing LDL levels, opposite of its estrogen counterparts. Medroxyprogesterone acetate is the most commonly used progestin preparation in the United States. Micronized or natural progesterone does not offer a clear-cut advantage, but appears less likely to cause mood changes. If given cyclically, a minimum dosage of five milligrams daily is required, with a minimum duration of ten days per month.
Conjugated estrogens / medroxyprogesterone acetate Prempro tablets Conjugated estrogens and conjugated estrogens / Premphase medroxyprogesterone acetate tablets
Ortho Prefest
AcGvella
FemHrt
Angeliq
Transdermal Combined Hormone Therapy Products Prepara1on Brand(s) Dose 0.05/0.14 mg & 0.05/0.25 mg (estradiol / norethindrone acetate, respecGvely) 1 patch 2x/wk 0.045/0.015 mg (estradiol / levonorgestrel, respecGvely) 1 patch weekly
CombiPatch
Androgens
Oral Estrogen/Testosterone Prepara1ons: Prepara1ons Benefits: May bone mineral density (BMD) Increased libido Increased psychological functioning Risks: Virilization / hirsutism Hepatotoxicity Decreased HDL cholesterol Prepara1ons Transdermal testosterone Brand(s) Androderm, Testoderm, Testoderm TTS AndroGel, TesGm Dose 2.5 mg6 mg/patch Apply 1 patch daily 25 mg/2.5 Gm/pkt & 50 mg/ Gm/pkt Apply once daily Oral Esteried estrogens/ oral methyltestosterone Oral Esteried estrogens/ oral methyltestosterone Brand(s) Estratest Estratest H.S. Dose 1.25 mg/2.5 mg tablets 1 tablet daily (3 wks on and 1 wk o) 0.625 mg/1.25 mg tablets 1-2 tablets at bedGme
Androgens
Injectable Testosterone Prepara1ons: Prepara1ons IM estradiol cypionate / testosterone cypionate Brand(s) Dose
2 mg/mL / 50 mg/mL vials Depotestadiol, (estradiol cypionate / Depotestogen, testosterone cypionate, respecGvely) DuoCyp Inject monthly
Benets and risks of androgens have both been demonstrated and various preparaGons have been idenGed. Benets of androgens include increased bone mineral density, increased libido, and improved psychological funcGoning for symptoms such as anxiety and depression. Risks of taking androgens as hormone therapy include virilizaGon, or hirsuGsm, which are infrequent and reversible. Hepatotoxicity has been found with high doses of androgens. Androgens may also decrease high-density lipoprotein (HDL) cholesterol. Topical and transdermal testosterone preparaGons are used daily.
For patients with complaints of only vaginal symptoms, treatment should be restricted to localized products. Local estrogen therapy is effective for patients with complaints of vaginal dryness, dyspareunia, and urinary frequency or urgency. Systemic products should be reserved for patients with vasomotor symptoms.
Other Clonidine 0.1-1.5mg orally daily 38-78% symptom reduction compared to 24-50% for placebo Transdermal clonidine (equivalent to 0.1mg daily) weekly patch 20-80% symptom reduction compared to 36% for placebo Gabapentin 900-2,700mg daily in divided doses 45% symptom reduction compared to 29% for placebo GU Atrophy: Lubricants, moisturizers, oils Urinary analgesics
For most symptomatic menopausal women, HT remains the most effective treatment when administered at the lowest effective dose for the shortest duration possible. However, various nonhormonal options are available for treating menopausal symptoms and bone loss in women who are unable or unwilling to take HT. For hot flashes, patients should avoid caffeine, alcohol, and spicy foods. Adjusting room temperature and dressing in layers may help as well. Although not medically proven, vitamin E and other herbal remedies may help in easing the hot flush symptoms. Case studies have also shown benefit for certain antidepressants like SSRIs and SNRIs since development of vasomotor symptoms seems to be related to the withdrawal of gonadotropins and the instability of serotonin and norepinephrine in the hypothalamus. Most of the studies involving SSRIs for relief of vasomotor symptoms have included paroxetine since it has the highest affinity for the norepinephrine receptor among the SSRIs.
Nutraceutical Options
Black cohosh (Cimicifuga racemosa) Remifenen Red clover isoflavones Promensil - 82 mg of isoflavones Romostil - 57 mg of isoflavones No clinically important effects on hot flashes or other symptoms of menopause
Most studies have failed to show significant, if any, difference between isoflavones such as red clover or the herb black cohosh. One study from by Van de Weijer et al. in 2002 of 80 mg of isoflavones versus placebo for 12 weeks found hot flashes significantly decreased in the treatment group relative to placebo; however, after a 16.7% decrease in hot flashes during a single blind screening phase, there was no further reduction in the placebo group. Phytoestrogens are substances found in many plants, such as soy plants, that have similar effects to estrogen. The evidence that phytoestrogens are helpful for menopausal women comes mostly from observational studies and epidemiologic studies of cultures whose diet is rich in phytoestrogens. The long-term adverse effects of phytoestrogen consumption are not known.
This list represents other options to consider instead of estrogen +/- progestin for the management of postmenopausal women. Close to 40% of postmenopausal women in the United States took hormone therapy prior to the release of the recent landmark trials. The purpose of healthy women taking long-term estrogen/progestin therapy is to preserve health and prevent disease. The results of these landmark studies provide strong evidence that the opposite is happening for important aspects of womens health, even if the absolute risks are low. Certain benefits such as prevention of osteoporosis and treatment of vasomotor symptoms are known and may be benefit from short-term HT. Postmenopausal women who have not had a hysterectomy should not receive estrogen only, as there is an unquestioned increased risk of endometrial cancer, and an increased risk of breast cancer and ovarian cancer as well.
Conclusion
Short-term therapy should still be considered for menopausal symptomatic treatment, although careful consideration of the risks and benefits should be observed Hormone therapy should not be offered for prevention of chronic disease Hormone therapy should not be recommended to women with a high risk of cardiovascular disease Long-term treatment is associated with an increased incidence of breast cancer All women should be counseled about the risks, benefits, and uncertainties of hormone therapy before deciding to start or stop treatment
Conclusion
The American Association of Clinical Endocrinoogists, American College of Obstetricians and Gynecologists, and the North American Menopause Society recommend against the use of HT for the primary or secondary prevention of chronic disease, especially cardiovascular disease. These organizations recommend caution in using HT solely to prevent osteoporosis and suggest considering alternate therapies. HT can be considered an acceptable treatment option for menopausal symptoms, but advise caution about the prolonged use of HT for the relief of symptoms. The American Heart Association now recommends against the use of HT for primary or secondary prevention of cardiovascular disease. For older patients who are many years removed from menopause and are still taking HT, consideration should be given to stopping therapy as it is clear that with longer duration of therapy comes increased risk of breast cancer. Although we have more information available regarding the risks and benefits of HT use in postmenopausal women, there are still several unanswered questions. More RCTs will need to be conducted to determine the risks and benefits of HT with regards to dose, formulation, patient population, and appropriate duration of HT among others.
. Resources
For additional information, see: Abraham D & Carpenter PC. Issues concerning androgen replacement therapy in postmenopausal women. Mayo Clinic Proceedings. 1997; 72:1051-1055. American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Menopause. Endocr Pract. 2006;12(3):317-337. American College of Obstetricians and Gynecologists. Hormone Therapy: Stroke. Obstet Gynecol. 2004;104(4 suppl): 97S-105S. American College of Physicians. Guidelines for counseling postmenopausal women about preventive hormone therapy. Ann Intern Med. 1993;117:1038-1041. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA. 2003;290(13):1739-1748. Ascott-Evans BH, et al. Alendronate Prevents Loss of Bone Density Associated With Discontinuation of Hormone Replacement Therapy. Arch Intern Med.2003;163:789-794. Boehringer SK. Estrogen Patches. Pharmacists Letter. Jan 2004;20:Detail Document #200108. Cardozo LD & Kelleher CJ. Sex hormones, the menopause, and urinary problems. Gynecol Endocrinol. 1995;9(1): 75-84.
Resources
Cauley JA, et al. Effects of Estrogen Plus Progestin on Risk of Fracture and Bone Mineral Density. JAMA. 2003;290:1729-1738. Chlebowski RT, et al. Estrogen Plus Progestin and Colorectal Cancer in Postmenopausal Women. NEJM. 2004;350 (10):991-1004. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289(24):3243-3253. Cirillo DJ, et al. Effect of Estrogen Therapy on Gallbladder Disease. JAMA. 2005;293(3):330-339. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Intern Med. 2006;166:772-780. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292:1573-1580. Davis SB & Burger HG. Androgens and the postmenopausal woman. Journal of Clinical Endocrinology and Metabolism. 1996;82:2759-2763. Espeland MA, et al. Conjugated Equine Estrogens and Global Cognitive Function in Postmenopausal Women. JAMA. 2004;291(24):2959-2968. Freeman R & Lewis RM. The therapeutic role of estrogensin postmenopausal women. Endocrinology and Metabolism Clinics of North America. 2004;33:771-789.
Resources
Hays J, et al. Effects of Estrogen plus Progestin on Health-Related Quality of Life. NEJM.2003;348:1839-1854. Hazzard WR., et al. Principles of geriatric medicine and gerontology. New York: McGraw-Hill. The Menopause and Hormone Replacement Therapy, pp. 867-876. Hodis HN & Mack, WJ. Postmenopausal Hormone Therapy and Cardiovascular Disease in Perspective. Clin Obstet Gynecol. 2008;51(3):564-580. Hoeger KM, et al. The Use of Androgens in Menopause. Clin Obstet Gynecol. 1999;42(4):883. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Intern Med. 2006;166:357-365. Hulley S, et al. Non-cardiovascular disease outcomes during 6.8 years of hormone therapy. JAMA. 2002;288:58-66. Hulley S, et al. Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women: Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA. 1998;280:605-613. Humphries KH and Gill S. Risks and benefits of hormone replacement therapy: The evidence speaks. CMAJ. 2003;168(8):1001-1010. Jenkins MR, Sikon AL. Update on nonhormonal approaches to menopausal management. Cleve Clin J Med. 2008;75 (4):S17-S24.
Resources
Kessel B & Kronenberg F. The role of complementary and alternative medicine in management of menopausal symptoms. Endocrinology and Metabolism Clinics of North America. 2004;33:717-739. Lund KJ. Menopause and the Menopausal Transition. Med Clin N Am. 2008;92:1253-1271. Manson JE, et al. Estrogen plus Progestin and the Risk of Coronary Heart Disease. NEJM. 2003;349(6):523-534. Martino S, Cauley JA, Barrett-Connor E, et al. Continuing outcomes relevant to Evista (CORE): Breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene. Journal of the National Cancer Institute. 2004;96:1751-1761. Nelson HD, et al. Postmenopausal Hormone Replacement Therapy. JAMA. 2002;288:872-881. Palacioz K. Hormone Replacement Therapy and Urinary Incontinence. Obstet Gynecol. 2001;97:116. Premarin & Prempro package inserts. Rapp SR, et al. Effect of Estrogen Plus Progestin on Global Cognitive Function in Postmenopausal Women. JAMA. 2003;289(20):2663-2672. Rossouw JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465-1477. Rymer J, et al. Making decisions about hormone replacement therapy. BMJ. 2003;326:322-326.
Resources
Scharf MB, et al. Effects of estrogen replacement therapy on rates of cyclic alternating patterns and hot-flush events during sleep in postmenopausal women: a pilot study. Clinical Therapeutics. 1997;19:308. Shamliyan TA, et al. Systematic Review: Randomized, Controlled Trials of Nonsurgical Treatments for Urinary Incontinence in Women. Ann Intern Med. 2008;148:459-473. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291(24):2947-2958. Shumaker SA, et al. Estrogen PLUS Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2003;289(20):2651-2662. Stefanick ML. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA. 2006;295(14):1647-1657. The North American Menopause Society. Estrogen and progestogen use in postmenopausal women: July 2008 position statement of The North American Menopause Society. Menopause. 2008;15(4):584-603. The North American Menopause Society. Treatment of menopause-associated vasomotor symptoms: position statement of The North American Menopause Society. Menopause. 2004;11(1):11-33.
Resources
The Womens Health Initiative Steering Committee. Effects of Conjugated Equine Estrogen in Postmenopausal Women With Hysterectomy. JAMA. 2004;291(14):1701-1712. Tice JA, et al. Phytoestrogen Supplements for the Treatment of Hot Flashes: The Isoflavone Clover Extract (ICE) Study. JAMA. 2003;290(2):207-214. Wassertheil-Smoller S, et al. Effect of Estrogen Plus Progestin on Stroke in Postmenopausal Women. JAMA. 2003;289:2673-2684. Writing Group for the Womens Health Initiative Investigators. Risks and Benefits of Estrogen Plus Progesterone in Health Postmenopausal Women. JAMA. 2002;288(3):321-333. Web Resources: Micromedex: www.micromedex.com Nelson H, et al. Postmenopausal Hormone Replacement Therapy for the Primary Prevention of Chronic Conditions: a summary of the evidence for the U.S. Preventive Services Task Force. www.preventiveservices.ahrq.gov North America Menopause Society: www.menopause.org Womens Health Initiative website: www.whi.org
Impotence
Learning Objectives:
By the end of this Review Concept you should be able to: Educate an elderly individual on the common clinical manifestations and risk factors for impotence. Recognize medications and health-conditions which may be associated with impotence. Construct a treatment plan for an elderly individual wishing to use non-pharmacologic/pharmacologic therapies for impotence.
The term impotence is often used synonymously with erectile dysfunction. It is important to distinguish between the two in order to understand how the disorder can be effectively treated. The term erectile dysfunction is used to describe the inability to attain or sustain an erection for satisfactory sexual performance. Impotence, on the other hand, is a broader term that includes sexual dysfunction secondary to factors other than the physical inability to achieve an erection, i.e. depression, loss of libido, & ejaculatory problems.
Etiology of Impotence
Psychogenic causes (10-30%) Vascular disease (70%) Arterial and venous atherosclerosis Hypertension Diabetes mellitus Endocrinopathy Neuropathy Neurological diseases Multiple sclerosis (MS) Pelvic surgery Cerebrovascular accident (CVA) Parkinson's disease Alcoholism Obesity1 Hypogonadism (rare) Peyronies disease
The incidence of impotence varies depending on its etiology. It is estimated that 322 million men will be diagnosed with ED by the year 2025. Ten to thirty percent of cases are psychogenic in nature and can be treated with proper counseling and guidance. Of the organic causes of impotence, seventy percent are associated with complications of arterial and venous atherosclerosis. It is also very common to have a combination of psychogenic and organic complications causing erectile dysfunction. Other causes include hypertension and smoking as both lead to vascular damage. Patients with diabetes have multiple risk factors for impotence, including endocrinopathy and neuropathy. In these patients, the prevalence of impotence rises dramatically with age. Neurological diseases, such as multiple sclerosis, pelvic surgery, CVA, and Parkinsons disease can induce impotence by interrupting autonomic fibers of the nerve endings. Peyronie's disease, a condition of uncertain cause, is characterized by a plaque, or hard lump, that forms on the penis. The plaque develops on the upper or lower side of the penis in layers containing erectile tissue. It begins as a localized inflammation and can develop into a hardened scar.
Latrogenic Impotence
Iatrogenic Impotence: occurs in ~ 25% of cases Classes of medications involved often mirror treatment for conditions known to cause impotence. These include:
From: Baldo O. Diagnosis and investigation of men with erectile dysfunction. J Men's Health Gend - March 2005; 2(1); 79-86
Latrogenic Impotence
Medications are known to interfere with the sexual response by either decreasing libido or the capability to attain an erection. Since the elderly may be taking a number of these agents for various medical conditions, drug-induced impotence can be a very real problem. A drug regimen review should always be performed in patients complaining of impotence. Iatrogenic impotence occurs in twenty-five percent of cases. It is often the medications used to treat the conditions originally causing impotence that lead to worsening of a patients impotence. Medications commonly implicated include antihypertensives, antidepressants, diuretics and anti-psychotics. While the list of potential impotence causing drugs is a long one, there are alternative regimens recognized as having fewer effects on male sexual function that may be substituted when appropriate. For example, 1st generation antihistamines can be replaced with the 2nd generation agents such as Loratadine. It should be noted that any diuretic that decreases intravascular volume may decrease penile arteriolar flow. Patients taking antihypertensives listed in the table at the end of this text may benefit from changing to ACEIs, alpha1 adrenergic antagonists (Terazosin, Doxazosin), CCBs and ARBs when appropriate.
Sexual sensory input is processed by hypothalamus Signals routed through sympathetic nervous system (SNS) and parasympathetic nervous system (PSNS) to prostate and urethra As sexual response heightens, sympathetic activity to penis decreases and parasympathetic activity increases Nitrous oxide increases cyclic guanidine monophosphate and depletes intracellular Ca, causing penile muscles to relax Penile arterial resistance decreases and inflow to penis increases six-fold. Decreased venous outflow produces pressure and erection.
The 4 phases of the sexual response are mediated by an intricate combination of the central, sympathetic and parasympathetic nervous systems. The 3 systems combined are responsible for the genital vasodilation initiated during the arousal phase of the sexual response. The plateau phase involves lubrication via the parasympathetic nervous system, while the orgasmic phase involves emissions via the sympathetic and parasympathetic nervous systems. Ejaculation is mediated entirely by the sympathetic system. During the resolution phase, decreases in arterial flow, intracavernosal pressure, and resistance to venous drainage produce flaccidity.
Diagnosing Impotence
Diagnostic testing: Blood pressure Prostate DRE Nocturnal penile tumescence Duplex Doppler ultrasound Somatosensory evoked potentials Caversonometry and caversonography Arteriography
The nocturnal penile tumescence (NPT) stamp test is a test that confirms the inability to achieve and maintain an erection.
From: http://www.nlm.nih.gov/medlineplus/ency/imagepages/8894.htm
Diagnosing Impotence
Lab Studies: Glucose Testosterone PSA Lipids FSH, LH & prolactin
Psychological assessment There are several tests available which aid in the diagnosis of impotence in the elderly male. Lab studies should include evaluation of glucose levels for diabetes, testosterone levels for hypogonadism, prostate-specific antigen for prostate cancer, and lipids for vascular disease, especially arthrosclerosis of the penile vasculature. Levels of folicle stimulating hormone, luteinizing hormone and prolactin should also be assessed to rule out pituitary disease. If the aforementioned tests dont identify the underlying cause of erectile dysfunction, there are other specialized diagnostic tests are available to specifically target impotence. For example, nocturnal penile tumescence refers to erections that occur at night. The ability to have an erection while sleeping indicates that a man is physically capable of this function. If a man cannot have an erection while awake, the cause may be due to physical problems, psychological factors, or both. For most men, erections while sleeping are the result of physical processes in the body rather than conscious control. The test is based on the fact that normal men have three to five involuntary night erections. Each erection lasts 20 to 30 minutes and men are often awakened by them. If a man has normal night time erections, it usually means there is no problem with the nerves, blood vessels or hormones.
Copyright 2011 American Society of Consultant Pharmacists
Diagnosing Impotence
Doppler ultrasound cavernosography is non invasive and can detect cavernosal abnormalities such as fibrosis and calcifications. During the physical exam, blood pressure and the degree of masculinization should be assessed along with an evaluation of the prostate for vascular and neurological disease. A detailed medical history should be obtained, noting risk factors such as elevated cholesterol, history of tobacco use, diabetes mellitus, hypertension, and pelvic and spinal trauma. A sexual history should also be documented to determine how long the man has been impotent.
Disadvantages: Bruising Pain Swelling (< 10% of cases) Interferes with spontaneity Requires manual dexterity
Penile Prostheses: Silicone-sheathed devices implanted into corpus cavernosa Possible complications include sepsis, erosion, migration, droop, and perineal pain Replacement required every 5-10 yrs
Sex Therapy: Open communication Partners roles and goals Partners expectations
Additional nonpharmacological treatments for impotence include penile prostheses, vascular surgery and sex therapy. Penile prostheses require surgical placement of silicone-sheathed devices into the corpora cavernosa. These devices can either be rigid or malleable and are manually inflated by the patient when an erection is needed. The disadvantages of prostheses include the requirement for anesthesia and surgery and a high incidence of complications such as sepsis, erosion, migration, droop, necrosis, perineal pain, and leaks. Use of antibacterialimpregnated or hydrophilic-coated prostheses reduces the risk for infection.The implant must also be replaced every 5-10 years. One of the last resorts for treatment is surgery. Vascular surgery has been more successful in Europe than in the United States, and involves arterial revascularization and venous ligation. Sex therapy is of course, the least invasive treatment option; focusing on the expectations, communication patterns and defined roles and goals of the couple.
Copyright 2011 American Society of Consultant Pharmacists
Selective Phosphodiesterase-5 (PDE-5) Inhibitors: Sildenafil Vardenafil Tadalafil Prostaglandins (intracorporeal or intraurethral) Papaverine (intracorporeal) Testosterone therapy
Other agents Topical alprostadil (Topiglan, Alprox-TD) Combination of aviptadil and phentolamine for intracavernosal injection (Invicorp)
From: Hatzimouratidis K and Hatzichristou DG. Erectile Dysfunction: Drugs. 2008; 68(2): 231-250.
Pharmacotherapy plays an important role in the treatment of impotence. The phosphodiesterase inhibitor, Sildenafil, emerged as the most popular first line oral agent for ED following its wildly successful introduction to the market in March of 1998. Six million prescriptions were dispensed to 3 million men in the first 9 months following its release. The success of sildenafil naturally led to the research and development of other phosphodiesterase inhibitors with faster onset, longer duration, and fewer side effects. Other older ED medications like prostaglandins and papaverine are administered via intracorporeal and intra urethral routes. These products are considered highly effective but are generally reserved for PDE-5 inhibitor refractory patients or those with contraindications to PDE-5 inhibitors , i.e. concomitant nitrate use. Testosterone therapy is normally indicated for impotence if the condition is due to hypogonadism. Advances in therapy for ED means that patients no longer should receive agents with questionable efficacy and known adverse events, such as yohimbine and trazodone.
Place in Therapy: First line, unless contraindicated Effective for vascular, neurogenic, and hormonal causes of ED
The American Urological Association supports the use of PDE5 inhibitors as first-line treatment for ED. Sildenafil was originally approved in 1998 as a breakthrough treatment for erectile dysfunction. Since then, two other PDE-5 inhibitors, vardenafil and tadalafil, have been approved. These agents have proven effective in patients with all three types of organic erectile dysfunction (vascular, neurogenic, or hormonal etiologies). There is insufficient evidence on the superiority of one agent over the others. Duration of action, patient-specific side-effects, as well as cost of the drug are usually the deciding factors as to which of these agents to choose.
Phosphodiesterase Inhibitors
Mechanism of Action: Selective inhibition of PDE5, causing prolonged cyclic guanosine monophophosphate (cGMP), release of nitric oxide, and relaxation of the smooth muscle in the penis.
Phosphodiesterase Inhibitors
Adverse Drug Reactions: PDE5 inhibitors can markedly increase the hypotensive effects of nitrates such as nitroglycerin; all of these drugs are contraindicated in patients taking nitrates for angina pectoris. In addition, they can all cause: Lowered blood pressure Headache Flushing Dyspepsia Mild visual disturbance (sildenafil and vardenafil) Death (if used with nitrates)
Phosphodiesterase Inhibitors
The result of PDE5 inhibition is prolonged cyclic guanosine monophosphate (cGMP) activity and the release of nitric oxide and the subsequent relaxation of the smooth muscle in the penis and to form an erection. All of these drugs have hypotensive properties, and are contraindicated for concurrent use with nitrates. Due to the hypotensive effects of PDE-5 inhibitors, it is recommended that all of these agents be used at the lowest dose possible when used in patients who are also taking non-selective alpha-blockers (doxazosin, terazosin) and the administration of these drugs should be separated by at least 4 hours. PDE5 inhibitors could also add to the hypotensive effect of other antihypertensive drugs. The risk of hypotension is especially pertinent in older men, many of whom take medications for high blood pressure, prostatic hyperplasia, or may experience angina.
Sildenafil
Initial dose: 25 mg in patients > 65 years old 50 mg in patients < 65 years old Administered 1 hour before intercourse High fat meals interfere with absorption
Drug Interactions: Nitrates: decreased BP; concomitant use is contraindicated Alpha-blockers: decreased BP; use the lowest sildenafil dose possible Cimetidine, erythromycin and ketoconazole all decreased sildenafil metabolism Rifampin can decrease effectiveness Can cause visual changes owing to affinity for PDE6 receptors found in high concentrations in the photoreceptor cells of the retina
Sildenafil
The recommended starting dose is for men over 65 years old is 25mg, about 60 minutes before sexual activity. High fat meals may decrease the effect of sildenafil. Duration of effect is approximately 1 hour. Like all existing PDE-5 inhibitors, concomitant use with nitrates is contraindicated and the risk of hypotension is increased when combined with alpha-blockers or other anti-hypertensives. The drug is metabolized in the liver, primarily by CYP3A4, and is subject to drug interactions when combined with 3A4 inhibitors or inducers. Additionally, sildenafil has some cross-reactivity with PDE-6, which may produce visual side effects.
Vardenafil
Initial dose: 5 mg in patients > 65 years old or moderate hepatic impairment 10 mg in patients < 65 years old Administered 1 hour before intercourse Drug Interactions: Nitrates: decreased BP; concomitant use is contraindicated Alpha-blockers: decreased BP; use the lowest vardenafil dose possible Indinavir, ritonivir, erythromycin and ketoconazole all decreased vardenafil metabolism QT prolongation; do not use with antiarrhythmics Can cause visual changes owing to affinity for PDE6 receptors found in high concentrations in the photoreceptor cells of the retina
Vardenafil
The recommended starting dose is 10 mg taken with or without food about 60 minutes before sexual activity. Duration of effect is approximately 1 hour. However, serum concentrations have been higher in men over 65 years old. Therefore a lower starting dose (5mg) should be considered in men > 65 years old. The drug is metabolized in the liver, primarily by CYP3A4 and should be considered in men with moderate hepatic impairment. Vardenafil may result in a slight prolongation of the QT interval (uncertain if this is clinically significant). Therefore vardenafil should not be used in patients with congenital QT prolongation or taken concurrently with antiarrhythmic drugs such as quinidine, procainamide, amiodarone, or sotalol. Due to drug interactions with 3A4 inhibitors, the manufacturer recommends using only 5 mg per day with coadministration of erythromycin or 200 mg of ketoconazole or itraconazole, 2.5 mg per day with indinavir, and 2.5 mg once every 3 days with ritonavir. Like sildenafil, vardenafil has some cross-reactivity with PDE-6, which may produce visual side effects.
Tadalafil
Initial dose: As needed use: 10 mg administered 30-60 minutes prior to sexual activity Once daily use: 2.5 mg daily, without regard to sexual activity Drug Interactions: Nitrates: decreased BP; concomitant use is contraindicated Alpha-blockers: decreased BP; use the lowest tadalafil dose possible Ritonivir and erythromycin decreased tadalafil metabolism
Tadalafil is unique because of its prolonged half-life, allowing a much longer time frame in which sexual intercourse can be initiated (24-36 hours). In 2008, the makers of tadalafil began marketing a once daily form, which can be taken every day without regard to timing of sexual activity. For as needed use, the recommended starting dose is 10 mg taken without regard to meals take 30-60 minutes minutes prior to intercourse. For once daily use, the recommended starting dose is 2.5 mg taken at approximately the same time every day, without regard to sexual activity. However, dose adjustment may be necessary in patients with renal or hepatic insufficiency.
Tadalafil
Tadalafil can increase hypotension and use is cautioned in patients taking any alpha1blocker except tamsulosin. Tadalafil apparently does not interact with other antihypertensive drugs. The potent CYP3A4 inhibitors ketoconazole and ritonavir have been shown to increase serum concentrations of tadalafil; other 3A4 inhibitors such as erythromycin, itraconazole and grapefruit juice probably could do so as well and should be avoided if possible or tadalafil dosage lowered.
Alprostadil (Caverject):
Initial Dose: 5 mcg (neurogenic cause) administers 1.25 mcg of alprostadil10 mcg (vascular cause) - administers 2.5 mcg of alprostadil
An injection of a vasodilator solution can be selfadministered directly into the corpus cavernosus before sex to achieve erection. No sexual stimulatin is needed, therefore it is the only effective treatment after major pelvic surgery without preservation of the neurovascular bundles of the corpora cavernosa. Caverject is the most commonly used drug for intracorporeal injections, which cause smooth muscles to relax and vasodilation to occur. Caverject is also the most effective monotherapy, with an efficacy of greater than 70%.
Unfortunately, administration may be difficult in patients who have dexterity issues, which limits its utility in older men. Initial dosages are five or ten micrograms, depending on the etiology of the condition. The dose of Caverject should be individualized to the patient by careful titration under close supervision of a physician. Side effects include pain which can be reduced if the injection is given slowly, over 30-60 seconds. A PGE-Phentolamine combination can be used, dosed at 3-8 micrograms. This combination, however, may cause painful burning as well. Papaverine is not FDA approved for erectile dysfunction, but has been used effectively for it since 1980. Papaverine also relaxes smooth muscle. Initial dosages may be increased up to sixty milligrams if patient does not respond.
Prostaglandins (MUSE)
Mechanism of action Absorbed through urethra, increases cAMP Administration Intraurethral suppository Dosing 125 mcg to 1000 mcg per erection (use the lowest effective dose)
Adverse Drug Reactions: Pain (penile and perineal) Urethral bleeding Syncope Penile burning sensation Vaginal burning in partner
Prostaglandins (MUSE)
Intraurethral insertion involves using an applicator with prostaglandin pellets placed in the urethra. Prostaglandin is then absorbed through the urethral mucosa into the corpus cavernosum, producing an erection. Initial dose titration should be administered under supervision of a physician to evaluate for response, proper technique, and evidence of hypotension. The average dose is five hundred micrograms per erection. The maximum frequency of use is 2 administrations per 24 hours. Side effects include penile pain.
Testosterone Therapy
Mechanism of action Replenishes bodys lack of natural testosterone in patients with hypogonadism
Dosing 200 mg IM every 2 weeks Testoderm patch: app. 6 mg patch daily to scrotum Testoderm-TSS: app. 5 mg patch daily to upper arm, back, or buttocks (do not apply to scrotum)
Side Effects Moodiness Aggression Excessive hair growth Lethargy Prostatic hypertrophy Oral: hepatic toxicity
Testosterone Therapy
Monitor Weight gain, edema, contact dermatitis (with patches) Follow-up Measurement of serum testosterone levels
Testosterone Therapy
Testosterone therapy is used to treat hypogonadism and can help improve energy, mood and sense of well being while enhancing erections. Treatment may be considered in men with ED who have a fasting morning testosterone level less than 220 ng/dL. Use of testosterone therapy is not indicated in patients with a normal serum testosterone level. Men receiving IM injections (which are given every 2-3 weeks) may suffer from changes in mood, energy and efficacy secondary to oscillating testosterone levels. Patches, on the other hand may be more tolerable by providing the patient with a more consistently normal level of testosterone. Transdermal and parenteral forms are more effective than oral therapy. Follow up treatment includes measurement of serum testosterone levels one and two weeks after intramuscular depot injection. Hepatic complications and hyperlipidemia are more commonly seen with oral formulations. The testoderm patch must be applied to a dry shaven scrotum of sufficient surface area to allow adequate adhesion. Men may find this more cumbersome to use than other testosterone patches.
Place in Therapy Questionable efficacy No longer recommended for use in ED Adverse Drug Reactions Yohimbine: Nausea Irritability Hypertension Tachycardia Trazodone Dizziness Somnolence Nausea Orthostatic hypotension
Due to advances over the past decade and questionable efficacy of these agents, patients should no longer receive yohimbine or trazodone for treatment of ED. Yohimbine was frequently prescribed as an oral treatment for ED prior to the advent of the PDE5 inhibitors. The American Urological Association and National Institute of Healths Consumers Panel question its efficacy and discourage its use. Results of a limited number of randomized, placebo-controlled clinical trials with trazodone have failed to show statistically significant efficacy.
Emerging Therapies
2nd Generation Phosphodiesterase Inhibitors Avanafil Phase II Udenafil Phase III, approved in Korea Mirodenafil Phase III, approved in Korea SLx-2101 Phase II
Possible advantages over existing PDE5 inhibitors: Greater specificity for PDE-5, and decreased risk with nitrates (Avanafil) Longer duration of action (SLx-2101 & Udenafil) Faster onset of action (Udenafil)
Emerging Therapies
Centrally acting agents Bremelanotide Phase II Mechanism of action: analogue of alpha melanocyte stimulating hormone Other agents Topical alprostadil (Topiglan, Alprox-TD) Phase III The quest continues for the ideal agent to manage ED. Second generation phosphodiesterase inhibitors are in phase II and III clinical trials. Advantages over the original PDE-5 inhibitors include greater specificity for PDE-5 and altered pharmacokinetics. A centrally acting compound, bremelanotide, is also being investigated. The effects of bremelanotide on sexual behavior, including penile erection, were demonstrated in laboratory animals. Because bremelanotide acts in the central nervous system, it will probably have little effect in those patients whose erectile dysfunction is due to neurogenic etiology, such as spinal cord injury. There are also several topical agents that are being investigated. These agents are designed to administer vasoactive substances without systemic adverse effects and avoiding the invasive nature of intraurethral or intercarvernous administration. In clinical trials, the most common adverse effect of these topical agents has been penile and vaginal irritation.
Summary
Current therapy has proven highly effective for the management of ED PDE-5 inhibitors are recommended for use as first-line therapy, unless contraindicated, for vascular, neurogenic, and hormonal etiologies Increased use of medications for ED may risk of transmission of sexually-transmitted diseases in older patients
The current management of ED has proven to be highly effective. However, increasing popularity of these agents have also ushered an unprecedented increase in HIV and sexually-transmitted diseases in a population that is stereotypically viewed as abstinent. According to the US Center for Disease Control, the incidence of HIV cases in the last decade has risen five-hundred percent among older adults. The rise in HIV and AIDS in older adults has been attributed to two factors: popularity of the PDE-5 inhibitors and lack of education regarding safe sex issues in the elderly. With this knowledge, pharmacists are encouraged to educate their patients that these agents do not prevent the transmission of sexually transmitted diseases and therefore should use safe-sex practices.
References
AACE Clinical Guidelines Sexual Dysfunction. http://www.aace.com/clin/guidelines/sexdysguid.pdf Borer J, Armstrong P. Proceedings of the 99th meeting of the Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee. May 29th and 30th, 2003. Circulation 2003; 107:e9052 Brock G, Bochinski D. Modern pharmacotherapy for erectile dysfunction: Curr Opin Urol 2001; 11:625-630. Chun J, Carson C. Physician-Patient Dialogue and Clinical Evaluation of Erectile Dysfunction: Urol Clin North Am 2001; 28(2) Dewire DM.Evaluation and treatment of erectile dysfunction: Am Fam Physician 1996; 53(6): 2101-2106. Dipiro Joseph T et al. editors. Pharmacotherapy, A Pathophysiologic Approach. 4th Ed New York: McGraw Hill; 2002 1511-1531 Doctors Guide Erectile Dysfunction Information and Resources. http://www.pslgroup.com/ERECTILE.HTM Eardley I. New oral therapies for the treatment of erectile dysfunction: BJU 1997; 81: 122-127.
References
Esposito, Katherine, MD et al, Effect of Lifestyle Changes on Erectile dysfunction in Obese Men: A Randomized Controlled Trial. JAMA. 2004;291:2978-2984. Fazio, Luke and Gerald Block. Erectile Dysfunction: Management Update. CMAJ. 2004;170(9) 1429-1437 Fink H et al. Sildenafil for Male Erectile Dysfunction: JAMA 2002; Reprinted in Arch Intern Med 2002 Jun 24; (162). Gentili A, Mulligan T. Sexual dysfunction in older adults. Clin Geriatr Med 1998; 14(2): 383-393. Gingell JC. New developments in self-injection therapy for erectile dysfunction. BJU 1998; 81: 599-603. Godschalk MF, Sison A, Mulligan T. Management of erectile dysfunction by the geriatrician: J Am Geriatr Soc 1997; 45: 1240-1246. Hakim LS, Goldstein I. Diabetic sexual dysfunction. Endocrinol Metab Clin North Am 1998; 25(2): 379-400. Hazzard WR, et al. Principles of geriatric medicine and gerontology. New York: McGraw-Hill, Erectile Dysfunction (Impotence), pp. 1251-1258. Hafez, E. S. E. and S.D. Hafez. Erectile Dysfunction: Anatomical Parameters, Etiology, Diagnosis, and Therapy. Archives of Andrology, 51:15-31, 2005. Hellstrom W. Sustained Efficacy and Tolerability of Vardenafil, a Highly Potent Slective Posphodiesterase type 5 Inhibitor: Urology Supplement 2003 April; (4A) Jackson SE, Lue TF. Erectile defection, Therapy health outcomes. New York:Elsevier Science, Inc; 1998.
Copyright 2011 American Society of Consultant Pharmacists
References
Kloner RA et al, Cardiovascular effects of tadalafil in patients on common antihypertensive therapies. Am J Cardiol 2003; 92 suppl 9A:47M Lue T. Erectile Dysfunction: N Engl J Med 2000 Jun;(324):24 Neal DR. Update on Pharmacological Causes and Treatment of Erectile Dysfunction: J Am Soc Consult Pharm supp Clinical Consult 1999; 7(14): 7-1 to 7-8.