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Homeostasis and The Stress Response 1 Homeostasis 2 Homeostasis • Definition: The tendency of an organism or a cell to regulate its internal conditions, usually by a system of feedback controls, so as to stabilize health and functioning, regardless of the outside changing conditions. http://www.biologyonline.org/dictionary/Homeostasis • Influences that tend to deregulate internal conditions are termed “stressors” – This is a different definition than we are used to hearing • Stressors can be physical, emotional, environmental, etc. • Compensatory mechanisms to counteract the effect(s) of stressors involve – – – – Autonomic nervous system Adrenal cortex Renin-angiotensin-aldosterone system (RAAS) Many others. 3 Stressors 4 Stressors 5 Three Components to Physiologic Stress Response 6 Three Components to Physiologic Stress Response 3. Adaptation response & return to homeostasis 1. Stressor 2. General adaptation syndrome 7 Neuroendocrine Pathways and Physiologic Responses to Stress Description 8 Neuroendrocrine Pathways and Physiologic Responses to Stress Description • Shows the different responses to stressors • May perceive stressor in the cerebral cortex or the stressor may be unconscious – Activating the RAS (the part of the brain that keeps up awake) – leads to increased muscle tension and alertness – Limbic system produces the emotional response • The locus ceruleus activates the ANS (sympathetic nervous system), which activates the adrenal medulla and the activation of the RAAS 9 Neuroendrocrine Pathways and Physiologic Responses to Stress Diagram 10 Neuroendrocrine Pathways and Physiologic Responses to Stress (Corticotropin Releasing Factor) (Adrenocorticotropic Hormone) Activation of the RAAS Adapted from Porth, 2011, Essentials of Pathophysiology,3rd ed., Lippincott, p. 213 11 Activation of the Sympathetic Nervous System (SNS) 12 Activation of the Sympathetic Nervous System (SNS) • Heart rate • Blood pressure • Cool skin – All of the blood is being shunted away form the skin to the skeletal muscle • Diaphoresis to keep body cool • Pupil dilation • Blood glucose to have fuel for muscle • Peristalsis • Urine output – Do not want to devote metabolic energy to urine formation 13 Release of Norepinephrine 14 Release of Norepinephrine Norepinephrine 1 1 2 1 Vasoconstriction of arteries and veins (↑Venous return to the heart/CO and ↑Blood Pressure) Pupil Dilation Heart rate Contractility Release of renin All of these increase blood pressure 15 Epinephrine Released by Adrenal Medulla 16 Epinephrine Released by Adrenal Medulla -Activates alpha 1 and alpha 2 as well as beta 1 2 2 receptors Vasoconstriction Epinephrine 1 1 Blood pressure 2 Pupil dilation Venous return/CO Heart rate Contractility Release of renin Dilation of skeletal muscle vascular beds and bronchi 17 Role of Epinephrine on B2 Receptors 18 Epinephrine 2 Lipolysis of triglycerides 2 Degradation of cholesterol to bile Salts Free fatty acids that can be used for ATP synthesis - maximizes energy production Cholesterol to be available for the repair of cell membranes 19 2 Skeletal Muscle Protein breakdown/amino acid release Epinephrine 2 Liver Gluconeogenesis Glycogen Breakdown Blood Glucose 20 Norepinephrine stimulates beta1 receptors to cause 21 Norepinephrine stimulates beta-1 receptors to cause: 25% 25% 25% 25% V as n en i se oc D ec re a R he a d of tio n tr ic on s re le a rt ra t ... bl oo ri d of tr ig ly e is ly s Li po se e es 1. Lipolysis of triglyerides – beta 2 2. Vasoconstriction of blood vessels alpha 3. Decreased heart rate – muscarinic receptors 4. Renin release 22 Release of Renin and ADH (Antidiuretic Hormone) 23 Release of Renin and ADH (Antidiuretic Hormone) • Renin is released in response to SNS stimulation of beta-1 receptors in the kidney – Release of renin initiates renin-angiotensin-aldosterone system (RAAS) – Angiotensin II causes vasoconstriction leading to Blood pressure – Aldosterone causes increased reabsorption of water in the kidneys causing venous return → cardiac output • Aldosterone has a steroid structure, like cortisol, and is referred to as a mineralocorticoid. ----------------------------------------------------------------------• ADH (antidiuretic hormone) is released from the posterior pituitary in response to SNS stimulation – ADH causes increased reabsorption of water in the kidneys causing venous return → cardiac output 24 Renin Angiotensin Aldosterone System (RAAS) Diagram 25 Renin Angiotensin Aldosterone System (RAAS) Diagram Must know this!!! Porth, 2011, Essentials of Pathophysiology, 3rd ed., Lippincott, p. 420. 26 Hypothalamus-Anterior Pituitary Function Diagram 27 Hypothalamus-Anterior Pituitary Function Porth, 2007, Essential of Pathophysiology, 2nd ed., Lippincott, p. 666 28 Hypothalamus-Anterior Pituitary Function Description 29 Hypothalamus-Anterior Pituitary Function Description • The hypothalamus and the anterior pituitary are important in the stress response • Cells release releasing factors that travel through the vessels and cause cells in the anterior pituitary to release tropic hormones – Go to target glands to release peripheral hormones • The hormone has a negative feedback on the anterior pituitary and the hypothalamus to decrease the hormone 30 Feedback Inhibition Diagram 31 Feedback Inhibition Diagram Porth, Essentials of Pathophysiology, 3rd ed., 2011, Lippincott, p.770. 32 Peripheral Glands Controlled by the Pituitary Diagram 33 Peripheral Glands Controlled by the Pituitary Porth, 2011, Essential of Pathophysiology, 3rd ed., Lippincott, p. 770 34 Regulation of Cortisol Synthesis and Secretion Description 35 Regulation of Cortisol Synthesis and Secretion Description • • • • Adrenals do not store glucocorticoids Amount released = amount made Regulated by negative feedback loop Circadian rhythm – bedtime, sleep, peak on awakening, during day • Stress increases CRH synthesis and release. • Some of the inputs into the hypothalamus include stress and circadian rhythms – Also regulated by negative feedback from cortisol in the periphery • Also acts on cells in the anterior pituitary – ACTH circulates all over the body, such as the adrenal cortex • Biological effects of cortisol are on nearly every body cell • Cortisol secretion is low at night, at its highest in the morning 36 Regulation of Cortisol Synthesis and Secretion Diagram 37 Regulation of Cortisol Synthesis and Secretion Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 711 38 Diurnal Secretion of Cortisol Diagram 39 Diurnal Secretion of Cortisol Stewart, Paul, 2003, The adrenal cortex in Larson, et al, eds., Williams’ Textbook of Endocrinology, Saunders. When we administer corticosteroids pharmacologically, we try to mimic this diurnal rhythm. 40 Cortisol Physiologic Effects 41 Cortisol Physiologic Effects • • • • • • Carbohydrate metabolism Fat metabolism Protein metabolism Cardiovascular Central nervous system Stress 42 Cortisol Carbohydrate Metabolism 43 Cortisol Carbohydrate Metabolism • Carbohydrate Metabolism – Gluconeogenesis – the synthesis of new glucose molecules in the liver – Peripheral glucose utilization in the periphery – Increased gluconeogenesis and decreased peripheral glucose utilization will increase glucose levels in the body – glucose uptake muscle/adipose tissue – Promote glucose storage (glycogen) All these make glucose more available to the brain! 44 Glucocorts 45 Glucocorts • Supplying the brain with glucose is essential for survival. • Glucocorts help meet this need with CHO metabolism thru the following 4 ways. – All 4 actions increase glucose availablility during fasting and thereby ensure the brain will not be deprived of its primary source of energy. • When present in chronically high levels for a prolonged period of time, glucocorts produce symptoms much like those of diabetics. • Pro metab: promote pro breakdown. – If present at high levels for prolonged pd of time, glucorts will cause a thinning of skin, muscle wasting, and negative nitrogen balance • Fat metab: glucocorts promote lipolysis (fat breakdown). – When present at high levels for an extended time, glucocorts cause fat redistribution, given the pt a potbelly, moon face, and buffalo hump on the back. 46 Cortisol Protein Metabolism 47 Cortisol Protein Metabolism • Promote catabolism • Amino acids provide substrate for hepatic gluconeogenesis 48 Cortisol Fat Metabolism 49 Cortisol Fat Metabolism • Promote lipolysis – Increases the amount of energy that is available to the cells • Free fatty acids provide substrate for the Krebs cycle. 50 Cortisol Cardiovascular System 51 Cortisol Cardiovascular System • Required for the integrity of the blood vessels, including their ability to constrict 52 Cortisol Central Nervous System 53 Cortisol Central Nervous System • Increases excitation • Euphoria • Alertness 54 Cortisol Stress Response 55 Cortisol Stress Response • Stress: – Stress increases CRH secretion by the hypothalamus • CRH secretion stimulates ACTH (adrenocorticotropic hormone) secretion, which increases cortisol secretion 56 Effect of Acute Stress 57 Effect of Acute Stress • Goals: survival, vigilance, alertness, arousal, aggression • Designed to be self-limiting and short term • Similar to the “Fight” or “flight” – SNS activation – shortest term • Activation of the HPA (hypothalamus pituitary adrenal) axis promotes energy utilization and availability of substrate for tissue repair. – longer term. – Even though this is longer term, it is not designed to be continually activated 58 Chronic Stress 59 Chronic Stress • Prolonged activation of the system • Stage of exhaustion may be reached of the system • Health problems may result 60 Chronic Activation of the Stress Response May Exacerbate Diseases 61 Chronic Activation of the Stress Response May Exacerbate Diseases Cardiovascular Heart disease, stroke Immune Autoimmune diseases GI Endocrine CNS Ulcers, irritable bowel syndrome, colitis, vomiting, diarrhea Diabetes mellitus, metabolic syndrome Fatigue, eating disorders, depression, insomnia, post-traumatic stress disorder 62 Coping and Adaptation Description 63 Coping and Adaptation Description • Humans have the capacity to adapt and cope with stressors based on a lot of different things • Very young and very old people do not respond to stress as well as middle-aged people • Hardiness – the ability to go on despite problems • It is harder to adapt to a sudden stressor 64 Coping and Adaptation Diagram 65 Coping and Adaptation Porth, 2011, Essentials of Pathophysiology, 3rd ed., Lippincott, p. 216. 66 Coping 67 Coping • The coping response can exaggerate or moderate the consequences of the stress response • Outcome is determined by coping strategies – Effective coping moderates stress – Ineffective coping exacerbates stress 68 Nursing Care and Stress 69 Nursing Care and Stress • “Nurses should put the patient in the best possible condition for nature to restore or preserve health, to prevent, or cure disease” (Florence Nightingale) – This is still performed today • Today’s hospital environment (stressful!) – Turbulence, frenzied pace, telephones, intercoms, electronic alarms, pagers, telemetry – The hospital environment is not very conducive to rest • Is the hospital a place of healing? 70 Types of Environments Diagrams 71 This Environment 72 Or this Environment… 73 Nurse’s Role in Dealing with Stress 74 Nurse’s Role in Dealing with Stress • Nurses can help patients deal with the stress of injury, disease, or psychological stressors –Augment the patient’s own methods of coping –Provide the means for adapting to stressors 75 Supportive Care 76 Supportive Care • Should be given to every patient • Maintain/restore homeostasis by monitoring fluid, electrolytes, blood pressure, heart rate, etc., and making necessary corrections. • Provide adequate nutrition to provide substrate for energy generation and repair/maintenance of tissues. • Provide appropriate sleep-wake cycles. – Postpone blood draws and other care – Darken the room as far as possible • Provide protection from stressful life events. – Appropriate visitors – Restful environment – Clear explanations and patience 77 Non-Pharmacologic Methods 78 Non-Pharmacologic Methods • Music therapy • Relaxation techniques • Guided imagery • Massage therapy • Biofeedback 79 Disorders Affecting the Stress Response: Hypothalamic Pituitary Adrenal Axis 80 Cushing’s Syndrome Glucocorticoid Excess 81 Cushing’s Syndrome Causes 82 Cushing’s Syndrome Causes • Primary causes • Secondary causes 83 Cushing’s Syndrome Primary Causes 84 Cushing’s Syndrome Primary Causes • Hypersecretion of ACTH by pituitary adenomas (benign tumors) (Cushing’s disease) • Hypersecretion of glucocorticoids by adrenal adenomas and carcinomas • These are rare – Hardly ever see primary Cushing’s syndrome 85 Cushing’s Syndrome Secondary Causes 86 Cushing’s Syndrome Secondary Causes • Caused by chronic administration of pharmacologic glucocorticoids (autoimmune diseases such as rheumatoid arthritis, organ transplant) • This is the most common cause of cushingoid changes 87 Signs/symptoms of Cushing’s Syndrome 88 Signs/symptoms of Cushing’s Syndrome • Obesity – Redistribution of fat to abdomen • Hyperglycemia/glycosuria • Hypertension • Fluid, electrolyte disturbances • Osteoporosis • Muscle weakness • Cataracts • Hirsutism • Menstrual irregularities • Decreased resistance to infection because steroids are immunosuppressant • Moon facies • “Buffalo hump” • Psychiatric changes 89 Cushing’s Syndrome Diagram 90 Signs & Symptoms of Cushing’s Syndrome Porth, 2007, Essentials of Pathophysiology, 2nd ed., Lippincott, p. 695. 91 Treatment for Cushing’s Syndrome 92 Treatment for Cushing’s Syndrome • Primary Cushing’s syndrome - surgical removal of diseased adrenal gland or diseased pituitary – If bilateral adrenalectomy is required, patient will need replacement with both glucocorticoids and mineralocorticoids (aldosterone) • Secondary Cushing’s syndrome – If glucocorticoid administration is the cause, decrease the dose as much as possible. 93 Etiology of Adrenal Insufficiency 94 Etiology of Adrenal Insufficiency • Primary hypoadrenalism • Secondary hypocortisolism 95 Etiology of Adrenal Insufficiency Primary Hypoadrenalism 96 Etiology of Adrenal Insufficiency Primary Hypoadrenalism • Primary hypoadrenalism – Addison’s disease – Can be contracted via infection, hemorrhage, surgical removal of the adrenal glands – Glucocorticoid deficiency, and possibly mineralocorticoid (aldosterone) insufficiency 97 Etiology of Adrenal Insufficiency Secondary Hypocorticolism 98 Etiology of Adrenal Insufficiency Secondary Hypocortisolism • Secondary hypocortisolism – Abrupt discontinuation of chronic pharmacologic glucocorticoids • This is the most common cause of adrenal insufficiency! – Hypopituitarism creates a deficiency in cortisol due to insufficient ACTH secretion • Glucocorticoid deficiency, but not mineralocorticoid – (Aldosterone is controlled by Angiotensin II not ACTH from the pituitary gland) 99 Regulation of Cortisol Synthesis and Secretion Description 100 Regulation of Cortisol Synthesis and Secretion Description • Pharmacologic steroids produce a negative feedback effect on the hypothalamus and pituitary. – CRH and ACTH are decreased to zero – Over time, the adrenal gland becomes less able to produce cortisol. • If pharmacologic steroids are discontinued abruptly, CRH and ACTH will increase but the adrenal cannot respond. – The person will be out of corticosteroids • Can be very dangerous • There may also be a problem with physiologic stress such as surgery, infection, etc. – extra steroids should be given. – Normally cortisol will increase – If a person is on pharmacologic steroids, the adrenal gland does not know about the stressor and cannot respond • Will have to increase steroids because the adrenal gland cannot increase its production of cortisol to meet the stressor 101 Regulation of Cortisol Synthesis and Secretion Diagram 102 Regulation of Cortisol Synthesis and Secretion Porth, 2011, Essentials of Pathophysiology, 3rd ed., Lippincott, p. 791. 103 Signs and Symptoms of Addison’s Disease 104 Signs and Symptoms of Addison’s Disease • Glucocorticoid deficiency – Hypoglycemia, anorexia, nausea, vomiting, diarrhea, anxiety, depression, hyperpigmentation • Mineralocorticoid deficiency – If deficiency is due to malfunctioning or absent adrenal gland – Fluid volume deficit, hyperkalemia, hyponatremia, orthostatic hypotension due to dehydration 105 Addisonian Crisis 106 Addisonian Crisis • Major complication, life threatening • May occur with abrupt discontinuation of pharmacologic steroids or failure to administer extra steroids to a steroid-dependent patient who has additional stress (surgery, trauma). – Severe hypotension – Hyponatremia – Dehydration – Hyperkalemia 107 Treatment of Addisonian Crisis 108 Treatment of Addisonian Crisis • Immediate replacement of cortisol with hydrocortisone • Hydrocortisone is fast acting and has both glucocorticoid and mineralocorticoid activity • May also need mineralocorticoid replacement as well as the steroids 109 Normal secretion of cortisol from the adrenal cortex is the HIGHEST at 110 Normal secretion of cortisol from the adrenal cortex is the HIGHEST at: 25% 25% t 12 m id n ig h pm 4: 00 n no o 12 A M 8:00 am 12 noon 4:00 pm 12 midnight 8: 00 1. 2. 3. 4. 25% 25% 111 Agents for Replacement Therapy in Adrenal Insufficiency: 112 Agents for Replacement Therapy in Adrenal Insufficiency: •These apply if the person has primary adrenal issues •Glucocorticoids •Mineralocorticoids 113 Fludrocortisone (Florinef) 114 Fludrocortisone (Florinef) • The only drug for aldosterone replacement – Is an aldosteorne agonist • Aldosterone replacement, but also has some glucocorticoid activity. • Most of the time, is given with a glucocorticoid. • Renal effects: – Like aldosterone, acts on the collecting ducts to promote Na+ reabsorption (H20 ) in exchange for K+, H+ • Cardiovascular effects (harmful effects with levels): – Promotes myocardial remodeling and fibrosis – Vascular fibrosis 115 Glucocorticoids 116 Glucocorticoids • Cortisol • Very commonly used • Physiologic vs. pharmacologic effects – Physiologic = low levels for replacement in primary Addison’s disease – Pharmacologic = high levels for immunosuppression (organ transplant) or antiinflammatory activity. • Pharmacological steroids are more commonly given in large doses Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 711 117 Oral Glucocorticoid Drugs Used to Treat Adrenal Insufficiency 118 Oral Glucocorticoid Drugs Used to Treat Adrenal Insufficiency • Hydrocortisone: has some mineralocorticoid activity. • Dexamethasone • Prednisone • These drugs will be discussed in detail in the section on steroids for non-endocrine disorders. • When used for adrenal insufficiency (steroid replacement), doses are low to produce physiologic levels and effects. 119 Hydrocortisone for Adrenal Insufficiency 120 Hydrocortisone for Adrenal Insufficiency • Replacement therapy – Oral hydrocortisone is ideal for chronic replacement therapy – Parenteral administration used for acute adrenal insufficiency and to supplement oral doses at times of stress – May suffice as sole therapy since it has mineralocorticoid activity – Dirt cheap! 121 High Dose Glucocorticoid Therapy for Non-Endocrine Disorders 122 High Dose Glucocorticoid Therapy for NonEndocrine Disorders • Glucocorticoids have powerful anti-inflammatory and immunosuppressive actions. – These do not occur at physiologic doses but at higher, pharmacologic doses. • When used at high doses for their anti-inflammatory or immunosuppressive effects, the physiologic effects are magnified and cause important side effects. • Non-endocrine use of glucocorticoids is much more common than use as replacement for adrenal insufficiency. 123 Anti-inflammatory/ Immunosuppressive Effects of Pharmacologic Doses of Glucocorticoids 124 Anti-inflammatory/Immunosuppressive Effects of Pharmacologic Doses of Glucocorticoids • Inhibit synthesis of inflammatory mediators – Prostaglandins, leukotrienes, histamine – Reduce swelling, warmth, redness, pain • Suppress infiltration of phagocytes – Damage from lysosomal enzymes is averted • Suppress proliferation of lymphocytes in response to the immune system – Reduce immune component of inflammation – This could be both good and bad 125 Therapeutic Use of Glucocorticoids in Nonendocrine Disorders 126 Therapeutic Use of Glucocorticoids in Nonendocrine Disorders • • • • • • • • Rheumatoid arthritis – intra-articular or systemic Systemic lupus erythematosus - oral Inflammatory bowel disease - oral Allergic conditions – topical or systemic Asthma – inhaled or systemic Cancer Suppression of allograft rejection Prevention of respiratory distress syndrome in preterm infants (administered to the mother in threatened preterm birth) – Promotes fetal lung maturation 127 “Local” Administration of Glucocorticoids 128 “Local” Administration of Glucocorticoids • Inhalation or intra-articular • On the skin • Since steroids are very lipid soluble, some of the locallyadministered dose will get into the bloodstream but concentrations will be lower than if it were administered systemically • Because blood levels are lower with these routes of administration, side effects are lessened. – Local administration is the best for avoiding side effects 129 Oral Dosing Guidelines 130 Oral Dosing Guidelines • For chronic conditions, usually start with low dose and increase until symptoms improve • Daily dosing: – Give entire dose before 9AM every morning (limits adrenal suppression since it coincides with the normal peak level of cortisol). – Some patients may require a 2nd dose in the afternoon. • Alternate day dosing: – May be possible in some patients as the 1st step in tapering – Reduces adrenal suppression, risk of growth retardation, overall toxicity 131 Steroid Use for Acute Conditions 132 Steroid Use for Acute Conditions • “Steroid pulse” is given at a high dose initially with tapering over a week or 2-week period. – Example: Oral prednisone, 60 mg. for 4 days, 50 mg for 2 days, 40 mg for 2 days, 30 mg. for 2 days and so on. • This type of regimen will not cause adrenal suppression. • Ex. poison ivy 133 Diurnal Secretion of Cortisol Diagram 134 Diurnal Secretion of Cortisol Stewart, Paul, 2003, The adrenal cortex in Larson, et al, eds., Williams’ Textbook of Endocrinology, Saunders. When we administer corticosteroids pharmacologically, we try to mimic this diurnal rhythm. 135 Adverse Reactions of Pharmacologic Glucocorticoid Therapy 136 Adverse Reactions of Pharmacologic Glucocorticoid Therapy • When taken chronically in large doses (non-endocrine disorders), there are a multiplicity of adverse effects that must be monitored and dealt with. – – – – – Metabolism Bone Fluids and electrolytes Immune system Eye problems • Cataracts • Glaucoma – Peptic ulcers – Growth retardation in children – Psychiatric side effects • Often the patient has to take a 2nd or 3rd drug to counteract the bad effects of the steroids. 137 Glucocorticoid Therapy Effects on Metabolism 138 Effects on Metabolism • Intensified effects of physiologic doses • Hyperglycemia/diabetes – This is a significant adverse effect that frequently results in the patient being treated for diabetes and experiencing the long-term complications of diabetes. • Suppression of protein synthesis • Fat deposits mobilized and redistributed (cushingoid habitus) • Osteoporosis 139 Glucocorticoid Therapy Effects on Bones: Osteoporosis 140 Glucocorticoid Therapy Effects on Bones: Osteoporosis Glucocorticoids cause bone loss by: • Suppression of bone formation by osteoblasts • Acceleration of bone resorption by osteoclasts • Reduction of intestinal absorption of calcium 141 Osteoporosis 142 Osteoporosis • Osteoporosis with resultant fractures is a frequent, serious complication of therapy • Ribs and vertebrae most affected • More likely to occur with systemic therapy (as opposed to inhaled or intra-articular uses) 143 Osteoporosis Prevention 144 Osteoporosis Prevention • Bone mineral density test prior to treatment • Use routes of administration that do not result in high blood levels (topical, inhalation, or intra-articular). • Patients should receive calcium and vitamin D supplements • Bisphosphate therapy (alendronate, etidronate) preserves bone by inhibiting osteoclastic bone resorption. – Although these drugs are approved for glucocorticoid-induced osteoporosis, they are not approved for osteoporosis prophylaxis. • Calcitonin inhibits osteoclasts – this drug is also not approved for osteoporosis prophylaxis. 145 Glucocorticoid Effects on Fluid and Electrolytes 146 Glucocorticoid Effects on Fluid and Electrolytes • Retention of water and sodium may result in hypertension and edema • Hypokalemia can lead to dysrhythmias • Precautions: – Consider restricting sodium intake – Consider adding potassium rich foods to diet, or administration of supplements – Monitor BP • Instruct patient to notify practitioner of fluid retention and palpitations (a sensation of rapid heart beat). 147 Glucocorticoid Effects on Immune System Infection 148 Glucocorticoid Effects on Immune System Infection • Immunosuppressant • Suppression of immune system increases susceptibility to infection: -New infection or reactivation of latent infection (TB) • Steroids prevent the inflammatory manifestations of infection such that fulminant infection may develop without detection. – The person may not develop a fever, redness, swelling, pain, etc. • Prevention and close monitoring are key – Pneumocystis carinii pneumonia common, therefore sulfamethoxazol/trimethoprim prophylaxis is recommended 149 Glucocorticoid Treatment and Myopathy 150 Glucocorticoid Treatment and Myopathy • Manifests as muscle weakness • Muscles of arms and legs affected most • Damage may prevent ambulation • If myopathy develops, dosage should be reduced 151 Glucocorticoids and the Development of Cataracts and Glaucoma 152 Glucocorticoids and the Development of Cataracts and Glaucoma • Extremely common complication • Cataracts are a common complication of long term therapy: – Eye examination every six months – Advise patient to contact provider with changes in vision • Oral glucocorticoids can cause glaucoma: – Usually develops rapidly, reverses within 2 weeks of cessation • However, the person should taper the dose 153 Glucocorticoids and Peptic Ulcer Disease 154 Glucocorticoids and Peptic Ulcer Disease • Glucocorticoids inhibit prostaglandin synthesis, augment secretion of gastric acid and pepsin, inhibit production of protective mucus, reduce gastric mucosal blood flow → GI ulceration • Risk increases with other ulcerogenic drugs, such as NSAIDS • Early detection crucial through examination for occult blood in the stool • Instruct patient to notify practitioner if stools become black (melana) 155 Glucocorticoids and Growth Retardation in Children 156 Glucocorticoids and Growth Retardation in Children • Probably as result of reduced DNA synthesis, decreased cell division • Assess height and weight regularly • Growth suppression may be minimized with alternate day therapy 157 Glucocorticoids and Psychiatric Side Effects 158 Glucocorticoids and Psychiatric Side Effects • Most people experience increased alertness, energy, etc. • Psychosis with hallucinations, mood changes, and other psychological disturbances is unusual. 159 Long Term Corticosteroid Therapy 160 Long Term Corticosteroid Therapy • Bypasses negative feedback loop and results in gradual loss of adrenal and pituitary hormone reserves; atrophy of ACTH secreting cell occurs. • Sudden withdrawal results in acute adrenal insufficiency: the most common cause of adrenal insufficiency. – Could be fatal • Patients on glucocorticoids greater than 2 weeks have some degree of HPA suppression. • Secondary adrenal insufficiency is prevented by gradual “weaning” the patient from these drugs over weeks to months. 161 Regulation of Cortisol Synthesis and Secretion Description 162 • Regulation of Cortisol Synthesis and Secretion Description Pharmacologic steroids produce a negative feedback effect on the hypothalamus and pituitary. – CRH and ACTH are decreased. – Over time, the adrenal gland becomes less able to produce cortisol. • If pharmacologic steroids are discontinued abruptly, CRH and ACTH will increase but the adrenal can’t respond. • There may also be a problem with physiologic stress such as surgery, infection, etc. – extra steroids should be given. • Have adrenal insufficiency because of negative feedback mechanism on pituitary and hypothalamus and adrenal gland cannot respond to CRH and ACTH 163 Regulation of Cortisol Synthesis and Secretion Diagram 164 Regulation of Cortisol Synthesis and Secretion Porth, 2011, Essentials of Pathophysiology, 3rd ed., Lippincott, p. 791. 165 Glucocorticoid Withdrawal 166 Glucocorticoid Withdrawal • Should be done slowly (“taper”) • Schedule is determined by degree of adrenal suppression • Strategies for weaning • Depending on the time the person has been on steroids and the dose used, the tapering period may be years or they may never be able to be completely weaned. 167 Strategies for Weaning People off of Glucocorticoids 168 Strategies for Weaning People off of Glucocorticoids • • • • • Multiple daily doses to single daily dose Institute alternate day dosing Taper gradually over months Continue to monitor, adjust dose Increase dose for major stressors, such as surgery • Even if steroids are discontinued, the patient may need supplementation in the event of a major stressor because the adrenal gland may be inadquate 169 Adrenal Suppression and Physiologic Stress 170 Adrenal Suppression and Physiologic Stress • Patient taking glucocorticoids long term require increased doses at times of stress • Patients should carry an identification to inform emergency personnel • Patients should always have emergency supply of glucocorticoids on hand 171 Pregnancy and Lactation 172 Pregnancy and Lactation • Use of steroids in pregnancy should be carefully weighed. – Animal studies show increased birth defects; no studies in humans. – Discontinuation of steroids could be serious for the mother in terms of re-exacerbation of a disease, rejection of an organ, adrenal insufficiency, etc. • Adrenal hypoplasia with adrenal insufficiency is a possibility in the infant due to the action of the steroids • Large doses over long term in a lactating woman could cause growth retardation or other adverse events in the baby – If these are necessary, perhaps the mother should not breast feed. 173 Preparations 174 Preparations • The half-life, mineralocorticoid potency (aldosterone activation), and glucocorticoid potency are important variables (Table 71.1 in Lehne). • Long-acting steroids (betamethasone and dexamethasone) are more potent than hydrocortisone. • Depot preparations are available for intra-articular and intramuscular injection (Table 71.2 in Lehne). 175 Integrative Body Functions II: Alterations in Temperature Regulation 176 Body Temperature Regulation 177 Body Temperature Regulation • Core body temp maintained • 36-37.5C (97-99.5 F) • Individual differences, diurnal variations • Lowest in the morning and then increases • Maximum body temperature is around 6pm 178 Normal Diurnal Variations in Body Temperature Diagram 179 Normal Diurnal Variations in Body Temperature Porth, 2011, Essentials of Pathophysiology, 3rd ed., Lippincott, p. 65. 180 Thermoregulatory Center 181 Thermoregulatory Center • Core body temp is regulated by the thermoregulatory center in hypothalamus. • The center receives input from cold and warm thermal receptors located throughout body and generates output responses that conserve body heat or increase dissipation. • Thermostatic set point is set so body core temperature is maintained within normal limits: – With increased temperature, heat-dissipating behaviors are stimulated – With decreased temperature, heat-producing 182 behaviors are stimulated Responses to Conserve Heat 183 Responses to Conserve Heat • Vasoconstriction of superficial blood vessels reduces heat loss from the skin into the environment. • Contraction of piloerector muscles that surround hairs on skin – if we had fur, it would be fluffed up to conserve heat. • Assumption of huddle position to conserve heat 184 Responses to Produce Heat 185 Responses to Produce Heat • Shivering – muscle movement produces heat • Increased production of epinephrine which increases the availability of glucose and free fatty acids for fuel. – As we burn fuel, we generate heat • Increased production of thyroid hormone, which increases metabolism. 186 Responses to Decrease Heat 187 Responses to Decrease Heat • Dilation of the superficial blood vessels – “Flushing” of skin and dissipation of heat – Transfer of heat to the body surface where it is lost through convection or radiation • Sweating – produces loss of heat through evaporation – Controlled by the SNS – Evaporative heat losses are dependent on ambient temperature and humidity – In temperatures greater than body temperature, evaporative heat loss is essential for control of body temperature. 188 Mechanisms of Fever Description 189 Mechanisms of Fever Description • The pyrogens cause the resetting of the thermostatic set point – Released by the inflammatory response – The set point is set to a higher level and the temperature-raising responses are initiated 190 Mechanisms of Fever Diagram 191 Mechanisms of Fever Porth, 2011, Essentials of Pathophysiology, 3rd ed., Lippincott, p. 68. 192 Fever Mechanisms 193 Fever Mechanisms • Elevation in body temperature that is caused by a cytokine-induced upward displacement of the set point of the hypothalamic thermoregulatory center. • Caused by a number of microorganisms and substances, “exogenous pyrogens” • Exogenous pyrogens induce host cells to produce fever-producing mediators, “endogenous pyrogens” – Interleukins, Prostaglandin E 194 Core Temperatures 195 Core Temperatures • Greater than 41C (105.8F) or less than 34C (93.2F) indicate the normal thermoregulation is impaired 196 Elevations of Temperature 197 Elevations of Temperature • Fever (pyrexia) • Hyperthermia • Neurogenic fever 198 Elevations of Temperature Fever 199 Elevations of Temperature Fever • Upward displacement of hypothalamic set point • Usually caused by inflammatory mediators like IL-1 or by bacterial products • In children over 6 mos or so and immunocompetent adults, we would expect to see a temperature of over about 100°F (37.8°C). 200 Elevations of Temperature Hyperthermia 201 Elevations of Temperature Hyperthermia • Set point is unchanged (unlike in fever when the set point is changed) – The mechanisms that control body temperature are ineffective in maintaining temperature within normal range when heat production may be excessive or when there is exposure to high ambient temperatures – Ex. status epilepticus, ambient temperatures are extremely high 202 Elevations of Temperature Neurogenic Fever 203 Elevations of Temperature Neurogenic Fever • Neurogenic Fever: Origin in CNS, caused by damage to hypothalamus; resistant to anti-pyretics – Seen in stroke or brain-injury patients 204 Caution Related to Temperature Changes 205 Caution Related to Temperature Changes • Certain individuals may not be able to mount a fullblown fever response! Therefore, we have to be careful in our evaluations of temperature elevations in these people. – Infants, especially newborns. – Immunosuppressed individuals • Chemotherapy • Organ transplant • HIV infection – Frail elderly 206 Purpose of Fever 207 Purpose of Fever • May not be harmful and may be helpful • “Cook” the poisons? • May enhance immune function • Inhibit microbial growth • If it is a low fever and the person is functioning fairly well, it is okay not to lower it immediately 208 Patterns of Fever 209 Patterns of Fever • Intermittent • Remittent • Sustained • Relapsing 210 Patterns of Fever Intermittent 211 Patterns of Fever Intermittent • Temp returns to normal every 24 hours • Seen in children a lot 212 Patterns of Fever Remittent 213 Patterns of Fever Remittent • Temp does not return to normal and varies a few degrees in either direction 214 Patterns of Fever Sustained 215 Patterns of Fever Sustained • Temp remains above normal with minimal variation. 216 Patterns of Fever Relapsing 217 Patterns of Fever Relapsing • One or more episodes of fever, each as long as several days, with one or more days of normal temps between. • Ex. malaria 218 Physiologic Behaviors of Fever 219 Physiologic Behaviors of Fever Set point ---> Chill Actual temp-> Plateau Defervescence Flush Chill Pre-dromal Defervescence Time • RR, HR, Sweating • metabolic rate, need for 02, use of body proteins for energy, metabolic acidosis •Headache •Changes in mentation 220 Treatment of Fever 221 Treatment of Fever • Fever is a manifestation of disease state, important to determine cause • Treat infection, condition causing fever • Modify environment • Support hypermetabolic state • Protect vulnerable organs 222 Anti-pyretics 223 Anti-pyretics • Aspirin, acetaminophen – Aspirin should not be used to treat fever in children! – Acetaminophen or ibuprofen would be the drugs of choice • Anti-pyretics alleviate discomforts and protect vulnerable organs • Anti-pyretics reset the hypothalamic temperature control center to a lower level by blocking activity of COX-2, thereby inhibiting pyrogen-induced synthesis of prostaglandins. 224 Heat Exhaustion 225 Heat Exhaustion • Heat exhaustion: related to loss of salt and water through the sweat. – Temp between 37.8 and 40°C but not terribly elevated – May be exhausted, sweating profusely – Treat with cooling, rehydration 226 Heat Stroke 227 Heat Stroke • Heat stroke: Severe life threatening failure of thermoregulatory mechanisms resulting in an excessive rise in body temp (> 40C, 104 F), absence of sweating, and loss of consciousness. – Common in elderly in non-air conditioned settings. – Also seen in military/police settings during excessive physical training on hot days. 228 Hypothermia 229 Hypothermia • Core temps less than 35C (93F) – Accidental: Environment – Controlled: Surgery • Lower the person’s metabolic rate in order to protect themselves • Those at risk for accidental hypothermia: – Infants, elderly, malnourished, alcohol/sedatives, hypothyroidism – Hikers, swimmers 230 Manifestations of Hypothermia 231 Manifestations of Hypothermia • Changes in mentation, poor coordination, slurred speech. • Intense shivering with mild hypothermia, but shivering decreases as hypothermia becomes more severe. • Vasoconstriction of surface vessels – pale, even blue. • Cold diuresis • Dehydration and elevated hematocrit (Hct) (increases viscosity) • In moderate to severe hypothermia, metabolic rate decreases significantly (this is why hypothermia is used in surgery). 232 Treatment of Hypothermia 233 Treatment of Hypothermia • Re-warming: – Passive: Remove the person from the cold environment, cover with blankets, warm fluids to drink, etc. – Active: Immerse in warm water, use a heating pad (careful!). When hiking/camping, get in a sleeping bag naked with another (warm) naked person. – Active core re-warming: heated fluids into the GI tract or peritoneal cavity, extracorporeal rewarming of blood. 234 Which of the following alters the hypothalamic temperature setpoint? 235 Which of the following alters the hypothalamic temperature set-point? l or tis o C rm ia yp o H rt he r yp e H th e m ia ve r Fever Hyperthermia Hypothermia Cortisol Fe 1. 2. 3. 4. 25% 25% 25% 25% 236 Integrative Functions III Thyroid 237 Thyroid Hormones Description 238 Thyroid Hormones Description • Thyroid hormone comes in two types – Triiodothyronine – Thyroxine • Get there using the amino acid tyrosine – Add iodine to create monoiodotryrosine and then add another iodine to create di and then hitch together a mono and a di to create T3 or two di to create T4 239 Thyroid Hormones Diagram 240 Guyton & Hall, Textbook of Medical Physiology, 10th ed., 2000, Saunders, p. 860. 241 Thyroid Hormones Description 242 Thyroid Hormones Description • Hormones are synthesized in cells in the ducts • The duct is not empty, but rather is filled with colloid (or thyroid globulin) – When the T3 and T4 have been synthesized they secrete them into the duct, where are hitched to the 243 Thyroid Hormones Diagram 244 245 Porth, 2011, Essential of Pathophysiology, 3rd ed., Lippincott, p. 783 Thyroid Hormone Receptors Description 246 Thyroid Hormone Receptors Description • Most body cells have thyroid receptors • The thyroid hormone receptor is a nuclear receptor that influences gene transcription. • Only T3 binds to the thyroid receptor – T4 must be converted to T3 inside the target cells before it will activate the receptor. • T3 and T4 are synthesized by the thyroid and are synthesized • Thyroid receptor that is activated by T3 influences the transcription of multiple genes, so it has multiple effects in many different cell types. • Thyroid receptor is a nuclear receptor, leading to synthesis to the proteins with a plethora of effects 247 Thyroid Hormone Receptors Diagram 248 249 Thyroid Hormone Effects 250 Thyroid Hormone Effects • • • • • • Regulates cell breakdown Stimulates metabolic rate Growth and development Cardiovascular system Gastrointestinal system Central nervous system 251 Thyroid Hormone Effects Regulation of Cell Breakdown 252 Thyroid Hormone Effects Regulation of Cell Breakdown • Thyroid hormone regulates protein, fat, and carbohydrate breakdown in all cells. • 1. • 2. • 3. • 4. Stimulates fat breakdown and release of free fatty acids. Decreases cholesterol and triglycerides. Stimulates carbohydrate metabolism. Stimulates protein breakdown. 253 Thyroid Hormone Effects Stimulation of Metabolic Rate 254 Thyroid Hormone Effects Stimulation of Metabolic Rate • Thyroid hormone stimulates the metabolic rate. • 1. • • 2. 3. Increases respiratory rate and oxygen utilization. Stimulates body heat production. Decreases body weight. 255 Thyroid Hormone Effects Cardiovascular System 256 Thyroid Hormone Effects Cardiovascular System • Thyroid hormone affects the cardiovascular system. 1. Increases blood flow and cardiac output. 2. Increases heart rate. 3. Increases the cardiac contractility. 257 Thyroid Hormone Effects Growth and Development 258 Thyroid Hormone Effects Growth and Development • Thyroid hormone is important in growth and development. 1. Promotes CNS development in utero 2. Stimulates growth hormone secretion and skeletal maturation - Previously women who were hypothyroidic gave birth to babies who were mentally retarded (cretins) 259 Thyroid Hormone Effects GI Tract 260 Thyroid Hormone Effects GI Tract • Thyroid hormone affects the GI tract. 1. Increases GI motility. 2. Increases secretion of digestive juices. 261 Thyroid Hormone Effects Central Nervous System 262 Thyroid Hormone Effects Central Nervous System • Thyroid hormone affects the CNS 1. Increases the speed of impulse conduction (can be estimated from deep tendon reflexes). 2. Increases neuronal activity in the CNS. 263 Hypothalamic-Pituitary-Thyroid Feedback 264 HypothalamicPituitary-Thyroid Feedback Porth, 2011, Essential of Pathophysiology, 3rd ed., Lippincott, p. 265 784 Considerable Lag Time Built into the Thyroid System 266 Considerable Lag Time Built into the Thyroid System Guyton & Hall, Textbook of Medical Physiology, 10th ed., 2000, Saunders, p. 861. 267 Both Hypo- and HyperThyroidism Come on Slowly and Have Vague, Systemic Symptoms 268 Both Hypo- and Hyper- Thyroidism Come on Slowly and Have Vague, Systemic Symptoms •Patients may not notice how severe the symptoms have become because they come on slowly •Caregivers may diagnose depression or a viral illness rather than thyroid disease. •Because it has systemic effects and is insidious •The thyroid may or may not be enlarged. 269 Screening for Thyroid Disease 270 Screening for Thyroid Disease •The TSH level is the accepted screening test. •If TSH is high or low, tests for T3 and T4 are obtained. •The diagnosis of hypo- or hyper- thyroidism is based on the combination of the TSH, T3 and T4 levels. •The practitioner must differentiate between a problem in the thyroid and a problem in the pituitary. 271 Primary Hypo or Hyper Thyroidism 272 Primary Hypo or Hyper Thyroidism • The thyroid is not following the directions of the pituitary but rather is acting autonomously • Hypothyroidism --- TSH is high (saying that T3 and T4 are low so need to make more so TSH is high) but T3 and T4 are low. • Hyperthyroidism --- TSH is low (pituitary says that there is too much T3 and T4 but the thyroid makes more anyway) but T3 and T4 are high. • In either case, the problem is in the thyroid. The pituitary is normal. 273 Secondary Hypo- or HyperThyroidism 274 Secondary Hypo- or Hyper- Thyroidism • The thyroid is doing what it is told by the pituitary but the pituitary is giving it the wrong directions • Hypothyroid --- TSH is low and T3 and T4 are also low. • Hyperthyroid --- TSH is high and T3 and T4 are also high. • In either case, the problem is in the pituitary. The thyroid is normal. • The pituitary is telling the thyroid the wrong thing 275 Pituitary Cause for Hypo- or Hyper- Thyroidism is Rare 276 Pituitary Cause for Hypo- or HyperThyroidism is Rare • Secondary hypothyroidism or hyperthyroidism is rare • Increased secretion of TSH by the pituitary is most commonly caused by a tumor that secretes TSH. • Decreased secretion of TSH by the pituitary could be caused by a tumor that does not secrete TSH and crowds out the TSH-producing cells. • Head trauma can cause ischemia or necrosis of the pituitary --- this might cause panhypopituitarism, a loss of all pituitary hormones. See “Interesting Articles section of “Course Documents” in Blackboard . 277 Common Cause of Hypo- or Hyper-Thyroidism 278 Common Cause of Hypo- or HyperThyroidism • Hypo- or Hyper- Thyroidism is most often caused by problems in the thyroid (primary hypo- or hyper- thyroidism) • Hypothyroidism is treated by thyroid hormone replacement therapy. • Hyperthyroidism is treated by ablation (getting rid of the thyroid) --- either surgical or with radioiodine 279 A patient's TSH is low and his/her T3 and T4 are high. What is wrong? 280 A patient's TSH is low and his/her T3 and T4 are high. What is wrong? 1. Hypothyroidism, pituitary cause 2. Hyperthyroidism, pituitary cause 3. Hypothyroidism, thyroid cause 4. Hyperthyroidism, thyroid cause ro id is . H yp er th y oi d ot hy r yp H .. is m ... .. ro id is . er th y yp H H yp ot hy r oi d is m ... 25% 25% 25% 25% 281 Thyroid Replacement Therapy 282 Thyroid Replacement Therapy •TSH levels are tested about 6 weeks after therapy has begun. •This must be done because of the lag time following the administration of the hormone •TSH levels should have fallen to normal. If not, the dose is increased and a TSH level obtained 6 weeks later. •“Normal” TSH levels are under debate. One clinic uses 1.3 μU/ml as the target level (Lehne gives 0.3-6 μU/ml as the normal range). 283 Thyroid Supplementation Drugs 284 Thyroid Supplementation Drugs Thyroid supplementation drugs T3 (liothyronine sodium) Cytomel, Triostat T4 (levothyroxine sodium) Synthroid, Levoxyl, Levothroid, generic T3 and T4 (liotrix) Thyrolar T3 and T4 (thyroid extract) Various (rarely prescribed for newly diagnosed pts.) 285 Thyroid Replacement Therapy Preferred Replacement Drugs 286 Thyroid Replacement Therapy Preferred Replacement Drugs • Pharmacodynamically speaking, all thyroid replacement preparations will result in elevation of T3 levels and amelioration of the hypothyroid state, but there are pharmacokinetic reasons to pick one replacement over another. • T4 is preferred because of its longer half-life. – Blood levels of thyroid hormone are more constant with T4 therapy, even if a dose is missed. – T4 is converted to T3 in the target cell. 287 Treatment of Hyperthyroidism Introduction 288 Treatment of Hyperthyroidism Introduction • Radioiodine, medical management, or surgical ablation. • Either may destroy too much or all of the gland and make the patient hypothyroid. • In this case, thyroid replacement would be given 289 Treatment of Hyperthyroidism Surgery 290 Treatment of Hyperthyroidism Surgery • While the patient is waiting for thyroid ablation, they must be given drugs that relieve symptoms. • This is necessary because the person does not do well in treatment if they are hyperthyroidic • If surgical ablation is planned, a euthyroid state should be achieved prior to operation to prevent the development of intraoperative thyroid storm. 291 Treatment of Hyperthyroidism Medications 292 Treatment of Hyperthyroidism Medications • Beta blockers can be used to block tremulousness, tachycardia, and anxiety. • Calcium channel blockers can be used to control heart rate. 293 Drug Treatment of Hyperthyroidism 294 Drug Treatment of Hyperthyroidism Drugs that affect the thyroid gland or thyroid hormone. Drug Block thyroid hormone synthesis? Block peripheral conversion of T4 to T3? Propylthiouracil (PTU) yes yes Methimazole yes no 295 Preferred Drug Treatment of Hyperthyroidism 296 Preferred Drug Treatment of Hyperthyroidism • Methimazole is usually preferred because of its longer half-life and because PTU sometimes causes very severe liver toxicity. • In some cases, especially thyroid storm, PTU would be preferred because of its ability to block the conversion of T4 to T3. 297 Which of the following medications blocks peripheral conversion of T4 to T3? 298 Which of the following medications blocks peripheral conversion of T4 to T3? 25% 25% 25% 25% di u m iu m in e ne so so d ol e ro x th y vo Le Li ot hy r on i et hi m az M yl th io ur ac il Propylthiouracil Methimazole Liothyronine sodium Levothyroxine sodium Pr op 1. 2. 3. 4. 299 Thyroid Storm Thyrotoxic Crisis 300 Thyroid Storm Thyrotoxic Crisis • Sudden worsening of hyperthyroidism due to increased release of thyroid hormones. • Symptoms such as tachycardia, cardiac failure, uncontrolled fever and delirium are of most concern. • As for hyperthyroidism, treatment consists of agents to block release of thyroid hormone, βblockers and/or calcium channel blockers to control heart rate, and supportive care. 301 Treatment for Thyroid Storm 302 Treatment for Thyroid Storm 1. Iodide may be given, which impairs release of thyroid hormone from the gland. Iodide is also given preoperatively in surgical ablation to prevent intraoperative thyroid storm. 2. Steroids are commonly given. – (Steroids also inhibit the conversion of T4 to T3) 303