ADRENOCORTICAL DYSFUNCTION

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Adrenal glands are small triangular shaped endocrine glands. There are two parts of adrenal glands. They are medulla and cortex. It releases two hormones epinephrine and nor nor epinephrine. Epinephrine and norepinephrine both constrict blood vessels and are released in anticipatory states and other times of increased emotion, causing such changes as elevated blood pressure; release of glucagon, insulin, and fatty acids into the blood; and increases in heart rate, sweating, metabolic rate, and peristaltic activity. The adrenal cortex synthesizes and secretes more than 30 different steroids and is responsible for the maintenance of several life-sustaining physiological activities. The steroids are divided into three major groups: glucocorticoids, mineralocorticoids, and androgens. Either increased levels or deficits of the adrenal hormones can produce various disorders. cushing's syndrome, called also primary aldosteronism, which is related to excessive secretion of aldosterone. In addison's disease there is an overall hypofunction of the adrenal cortex, resulting in insufficient production of all three groups of adrenocortical hormones. adrenogenital syndrome, which is usually caused by a tumor of the adrenal cortex, results from excessive secretion of androgens.

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PREPARED BY: NAMRATA. DESAI SEM II M.PHARM CLINICAL PHARMACY nirma university 13MPH704 :

PREPARED BY: NAMRATA. DESAI SEM II M.PHARM CLINICAL PHARMACY nirma university 13MPH704 ADRENOCORTICAL DYSFUNCTION

AGENDA:

AGENDA Anatomy and physiology of adrenal Regulation of adrenal glands Adrenal dysfunction Cushing’s syndrome Addison Disease

ANATOMY AND PHYSIOLOGY:

ANATOMY AND PHYSIOLOGY

ANATOMY AND PHYSIOLOGY: :

ANATOMY AND PHYSIOLOGY: Adrenal glands are located on the top of each kidney. So it is also called as suprarenal gland. In human, the right adrenal gland is triangular shaped while the left adrenal gland is semilunar shaped. Adrenal gland are responsible for releasing hormones through the synthesis of corticosteroids such as cortisol and catecholamine’s such as adrenaline and nor adrenaline. These endocrine glands also produce androgens in their innermost cortical layer.

REGULATION OF ADRENAL GLANDS:

REGULATION OF ADRENAL GLANDS

REGULATION OF ADRENAL GLANDS: :

REGULATION OF ADRENAL GLANDS: Adrenal cortex is divided into three zones: Zona glomerulosa Zona fasciculate Zona reticularis  

Zona glomerulosa: :

Zona glomerulosa : Outermost layer The main site for the production of aldesterone , a mineralocorticoid by the action of enzyme aldesterone synthase . Aldosterone is responsible for the long term regulation of BP.Aldesterone effects are on the distal convulated tubule and collecting duct of the kidney where it causes Na+ reabsorption and excretion of K+ and H+ ions . Angiotensin II originates from plasmatic angiotensin I after the conversion of angiotensinogen by renin produced by guxtaglomerular cells of the kidney.

Zona fasciculate: :

Zona fasciculate: Situated between the glomerulosa and reticularis . Zona fasciculate is responsible for producing glucocorticoids, such as corticosterone and cortisol in humans. Cortisol is the main glucocorticoid under normal conditions and its actions include mobilization of fats, proteins and carbohydrates. Cortisol enhances the activity of other hormones including glucagon and catecholamine’s.

Zona reticularis: :

Zona reticularis : Innermost cortical layer, produces androgens mainly dehydroepiandrosterone , androstenedione .

ADRENAL DYSFUNCTION:

ADRENAL DYSFUNCTION DECREASED FUNCTION: Adrenal insufficiency Low cortisol, aldesterone Eg: Addison disease INCREASED FUNCTION: Cushing syndrome High Cortisol Hyperaldosteronism High aldestrone Pheochromocytoma High catecholamine

CUSHING SYNDROME:

CUSHING SYNDROME Cushing syndrome is a disorder caused by persistent glucocorticoids excess. Hypercortisolism.

ETIOLOGY :

ETIOLOGY ACTH-secreting tumor of the pituitary (Cushing’s disease) excess secretion of cortisol by a neoplasm within the adrenal cortex excessive or prolonged administration of exogenous steroids Endogenous glucocorticoid administration Frequency Age Sex Morbidity and Mortality

PATHOPHYSIOLOGY:

PATHOPHYSIOLOGY ACTH-dependent (Pseudo-CS) Pituitary (CD) (70%) Microadenomas (95%) Macroadenomas (5%) Ectopic ACTH or CRH (10%) Small cell lung ca Carcinoids: lung, pancreas, thymus ACTH-independent (Factitious) Unilateral Adrenal adenoma (10%) Adrenal carcinoma (5%) Bilateral Macronodular Hyperplasia (AIMAH) (<2%) Primary pigmented Micronodular Adrenal disease (PPNAD) (<2%)

SIGNS AND SYMPTOMS:

SIGNS AND SYMPTOMS Weight gain and obesity Moon face, plethora Buffalo hump Hirsutism Muscular weakness, especially proximal Malaise Depression, psychosis and mood changes Skin and hair thinning

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Oligomenorrhoea or amenorrhea in females Striae, acne, bruising Polyuria, nocturia Decreased libido and impotence in males Hypertension Diabetes or impaired glucose tolerance Osteoporosis Less common peptic ulceration occurs with and without symptoms.

FREQUECY OF SIGN AND SYMPTOMS OF CUSHING SYNDROME:

FREQUECY OF SIGN AND SYMPTOMS OF CUSHING SYNDROME SIGN AND SYMPTOMS OCCURRENCE % SIGN AND SYMPTOMS OCCURENCE % Central obesity 94 Easy bruisability 60 Hypertension 82 Osteoporosis 60 Glucose intolerance 80 Personality changes 55 Hirsutism 75 Acne 50 Amenorrhea or impotency 75 Edema 50 Purple striae 65 Headache 40 Plethoric faces 60 Poor wound healing 40

DIAGNOSIS:

DIAGNOSIS Obtain a careful history to exclude exogenous glucocorticoid use. Perform at least two first-line biochemical tests to obtain the diagnosis: Urine free cortisol (UFC) (at least two measurements) Late-night salivary cortisol (two measurements) 1-mg overnight Dexamethasone Suppression Test (DST) Longer low-dose Dexamethasone Suppression Test (LDDST) (2 mg/d for 48 h) Dexamethasone - CRH test

ALGORITHM FOR TESTING:

ALGORITHM FOR TESTING

DIFFERENTIAL DIAGNOSIS:

DIFFERENTIAL DIAGNOSIS Plasma ACTH Corticotropin-Releasing Hormone Stimulation Test Inferior Petrosal Sinus Catheterization Metyrapone Test Radiologic Imaging

TREATMENT:

TREATMENT PHARMACOLOGICAL THERAPY MEDICATIONS DOSAGE Ketoconazole a , b (Nizoral) Initial: 200 mg tid MD: 300–400 mg tid Metyrapone (Metopirone) Initial: 250 mg daily MD: 500–750 mg tid-qid Aminoglutethimide c (Cytodren) 250 mg bid- tid Mitotane b (Lysodren) Initial: 500 mg at bedtime MD: 2–4 g/d (one-half at bedtime) Etomidate ( Amidate ) 0.3 mg/kg/h IV

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MEDICATIONS DOSAGE Bromocriptine (Parlodel) 3.75–30 mg daily Cyproheptadine (Periactin ) Initial: 8 mg daily MD: Up to 24 mg daily Valproate (Depakene) 200–400 mg tid Mifepristone ( Mifeprex ) 400 mg daily

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NON PHARMACOLOGICAL THERAPY: Repeat surgery, Radiation therapy, Adrenalectomy. Early repeat transphenoidal surgery including the endoscopic technique may be worthwhile in a significant proportion of patients, at the expense of increased likelihood of hypopituitarism. ALTERNATIVE THERAPY: Numerous alternative therapies, including KH3, DHEA, vitamin C, phosphatidylserine, and melatonin.

CASE STUDY:

CASE STUDY 41 yr woman referred by her family doctor with fatigue and weight gain. PMH significant for DM (1year), hypercholesterolemia, and HTN resistant to 2 medications. She was followed for “subclinical hyperthyroidism”. Meds: Pravachol, Glucophage, Potassium, Ramipril, Metoprolol. Laboratory data Sodium= 135, K=3.3 BUN, Cr N Glucose=12.4 WBC=10.7 TSH=0.1 (0.3-5) , N FT4

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ROS and P/E: Alterations in physical habitus with 50lbs wt gain over 1 year mainly in abdo area. Severe insomnia, depression and difficulty concentrating. Very evident dorsocervical and supraclavicular fat pads. Round, plethoric face Wasted extremities with proximal muscle weakness Abdominal striae and hyperpigmentation Tender thoracic spine to palpation at T12

ADDISON’S DISEASE:

ADDISON’S DISEASE

DESCRIPTION:

DESCRIPTION Adrenal insufficiency is an endocrine or hormonal—disorder that occurs when the adrenal glands do not produce enough of certain hormones. Impairment in synthesis and/or release of adrenocortical hormones.

Diagram of Normal Feedback Loop:

Diagram of Normal Feedback Loop Target tissue Hormone of target tissue

Negative Feedback Loops:

Within a normal negative feedback loop involving the adrenal cortex the following would happen: The hypothalamus releases hypothalamic inhibitory or releasing hormones to the anterior pituitary. The anterior pituitary then releases ACTH to the adrenal cortex. The adrenal cortex will then release Glucocorticoids (to raise blood glucose levels or to replenish glucose during or after stressful situations) or Mineralocorticoids (to reabsorb sodium and excrete potassium in order to balance water in the body). When their functions are completed, the target tissues of the hormones will release their own hormones back to the hypothalamus in order to stop the release of hormones to affect the body. This represents a negative feedback loop in which the mechanism fluctuates around homeostasis. Negative Feedback Loops

DIAGRAM OF ADDISON’S DISEASE NEGATIVE FEEDBACK LOOP :

DIAGRAM OF ADDISON’S DISEASE NEGATIVE FEEDBACK LOOP Excessive and ineffective amounts of ACTH Adrenal cortex hormones are not released

Negative Feedback Loops (Continued):

In Addison’s diseases, the feedback loop is disrupted. The anterior pituitary releases excessive yet ineffective amounts of ACTH which is supposed to stimulate the adrenal cortex. The adrenal cortex as a result is affected negatively and does not release Glucocorticoids or Mineralocorticoids. Since Glucocorticoids are not produced, glucose cannot be replenished when stressful situations occur. Since Mineralocorticoids are not produced, there is a lack of sodium and water in the body thus leading to severe dehydration. Also, because ACTH exists in excessive yet ineffective amounts, bronzing of the skin occurs because ACTH is linked to melanin production. Negative Feedback Loops (Continued)

ETIOLOGY:

ETIOLOGY Primary insufficiency: Idiopathic (Addison disease) Tuberculosis Fungal infections Adrenal hemorrhage Congenital adrenal hypoplasia Sarcoidosis Amyloidosis Metastatic neoplasia Others (Age and Sex)

PowerPoint Presentation:

Secondary adrenal insufficiency : Inadequate ACTH secretion by the pituitary Iatrogenic After exogenous glucocorticoids After the cure of Cushing syndrome (removing endogenous glucocorticoids) Hypothalamic and pituitary lesions Drug induced

SIGNS AND SYMPTOMS:

SIGNS AND SYMPTOMS Weakness Skin Mucous membrane and skin pigmentation, darkening of hair freckling, vitiligo, pigment accentuation at nipples, and friction areas, pigment concentration in skin increases and in scars Loss of weight, emaciation, anorexia, vomiting, diarrhea Salt craving Hypoglycemic episodes Decreased tolerance for stress

PowerPoint Presentation:

Hypotension (less than 110/70 mm Hg) and orthostasis Dehydration, hypovolemia, and hyperkalemia Decreased serum sodium and chloride levels Personality changes (irritability and restlessness) Loss of axillary and pubic hair in women owing to decreased androgen production. Blood count abnormalities (e.g., normocytic, normochromic anemia, relative lymphocytosis, neutrophilia, eosinophilia)

This is a caseating granuloma of tuberculosis in the adrenal gland. tuberculosis used to be the most common cause of chronic adrenal insufficiency. Now, idiopathic (presumably autoimmune) Addison's disease is much more often the cause for chronic adrenal insufficiency.:

T his is a caseating granuloma of tuberculosis in the adrenal gland. tuberculosis used to be the most common cause of chronic adrenal insufficiency. Now, idiopathic (presumably autoimmune) Addison's disease is much more often the cause for chronic adrenal insufficiency.

DIAGNOSIS:

DIAGNOSIS Screening tests include: complete blood count with differential chest radiograph, serum biochemistries, renal function, urinalysis, and skin testing. Basal serum cortisol Short ACTH Stimulation Test

DIFFERENTIAL DIAGNOSIS:

DIFFERENTIAL DIAGNOSIS Basal Plasma ACTH 2-Day ACTH Stimulation Test Short Metyrapone Test Insulin-Induced Hypoglycemia OTHER DIAGNOSTIC TEST: Adrenal CT MRI Corticotropin-releasing hormone test

TREATMENT:

TREATMENT The goals of pharmacotherapy are to reduce morbidity and to prevent complications e.g. adrenal crisis; Empiric glucocorticoid replacement therapy and supportive therapy must be initiated . Hydrocortisone is the drug of choice for the acute treatment of an Addisonian crisis or for short-term parenteral use; Dexamethasone may be substituted to avoid confounding the results of an anticipated ACTH stimulation test. Mineralocorticoid deficiency is treated with saline and fluid loading; Specific aldesterone replacement therapy is not effective since it takes several days for the sodium-retaining effects to be apparent. Once the patient is stabilized, intravenous fluids are continued at a lower rate for another 1 to 2 days. Mineralocorticoid replacement therapy with Fludrocortisone is started when the patient is stable and able to take oral medications.

NON PHARMACOLOGICAL THERAPY:

NON PHARMACOLOGICAL THERAPY Liberalizing the dietary salt intake Avoidance of sodium-wasting diuretics and spironolactone. However, hypertensive patients should be maintained on salt-restricted diets.

CASE PRESENTATION:

CASE PRESENTATION History: a) Chief complaint: Nausea/ vomiting for 4 days. HPI: Patient c/o n/v intermittently for last 9 months, almost all day for the last 4 days, along with progressive weakness, fatigue, poor appetite, and myalgias . Denies fever, diarrhea, abd . pain, dysuria . Pt. went to MD 2 wks ago gave him Tigan and Prilosec witch made no change. Medications: Tigan , prilosec .

PowerPoint Presentation:

Review of systems: + weight loss 4 lbs/2 wks., dizziness, SOB, cough and sputum. Diarrhea, polyuria , polydipsia , seizures, hallucinations, depression. Skin: decreased skin turgor with some increased pigmentation on elbows. LABS: CBC: WBC 10.1, HBG 15, HCT 43, Pl. 408 CMP: Na 112, K 7.0, Cl 82, CO2 14, BUN 40, Cr. 1.4, Ca 10.8, Gap 16 Serum Osml . 249 UA: SG 1.005, Osm 286, Na 64, K 13.6 Screen: Baseline cortisol, ACTH and aldosterone levels, then give ACTH measure cortisol and aldos . At 30 and 60 min.

REFERENCES:

REFERENCES Marie A Chisholm, Barbara G Wells, Terry L Schwinghammer , Patrick M Malone, Jill M Kolesar , John C Rotschafer , Joseph T Dipiro , PHARMACOTHERAPY PRINCIPLES & PRACTICE, The McGraw-Hill Companies, 2008,685-700. R A.Helms , D J.Quan , E T Herfindal , D R.Gourley , Textbook of Therapeutics-Drug & Disease Management, 8th edition, Lippincott Williams & Wilkins, 961 – 980.

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