ALDOSTERONE PPT

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aldosterone:

aldosterone BY DR SHASHIDHAR

The Adrenal Gland:

The Adrenal Gland Anatomy was first described in 1563. Is located above (or attached to) the upper pole of the kidney. Is pyramidal in structure and weights about four grams. Consists of the adrenal cortex and adrenal medulla Activities are regulation of fluid volume and stress response

The Adrenal Gland:

The Adrenal Gland Anatomy was first described in 1563. Is located above (or attached to) the upper pole of the kidney. Is pyramidal in structure and weights about four grams. Consists of the adrenal cortex and adrenal medulla Activities are regulation of fluid volume and stress response

Adrenal Gland :

Adrenal Gland Cortex zona glomerulosa mineralocorticoids - aldosterone zona fasciculata glucocorticoids - cortisol zona reticularis androgens- estrogen, progesterone, testosterone Medulla norepinephrine , epinephrine

Adrenal Histology:

Adrenal Histology

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Adrenal Cortex Hormones produced by the adrenal cortex are referred to as corticosteroids. These comprise mineralocorticoids, glucocorticoids and androgens. The cortex is divided into three regions: zona glomerulosa zona fasciculata zona reticularis

Zona Glomerulosa:

Zona Glomerulosa Outermost zone – just below the adrenal capsule Secretes mineralocorticoids . Mineralocorticoids are aptly termed as they are involved in regulation of electrolytes in ECF. The naturally synthesized mineralocorticoid of most importance is aldosterone.

Zona Fasciculata:

Zona Fasciculata Middle zone – between the glomerulosa and reticularis Primary secretion is glucocorticoids. Glucocorticoids, as the term implies, are involved the increasing of blood glucose levels. However they have additional effects in protein and fat metabolism. The naturally synthesized glucocorticoid of most importance is cortisol.

Zona Reticularis:

Zona Reticularis Innermost zone – between the fasciculata and medulla Primary secretion is androgens. Androgenic hormones exhibit approximately the same effects as the male sex hormone – testosterone. NB.: Overlap in the secretions of androgens and glucocorticoids exist between the fasciculata and reticularis.

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ADRENAL MEDULLA Embryologically derived from pheochromoblasts Differentiate into modified neuronal cells HORMONES 1. Epinephrine 2. Norepinephrine more gland than nerve chromaffin cells

Adrenal Cortex: Steroid Hormone Production:

Adrenal Cortex: Steroid Hormone Production Figure 23-2: Synthesis pathways of steroid hormones pregnenolone 11 deoxycorticosterone 17 alpha Hydroxy pregnen 17 alpha hydroxy progesterone 11 deoxycortisol

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Aldosterone A steroid hormone Essential for life also called as LIFE SAVING HORMONE Responsible for regulating Na + reabsorption in the distal tubule and the cortical collecting duct

ALDOSTERONE:

ALDOSTERONE Free aldosterone comprises 30–50% of its total plasma concentration Short half-life, 15-20 minutes Inactivated in the liver, with formation of tetrahydroaldosterone

Mechanism of action:

Mechanism of action

Secreation and regulation:

Secreation and regulation

Regulation of Aldosterone Secretion:

Regulation of Aldosterone Secretion

Aldosteronism :

Aldosteronism Primary aldosteronism Secondary aldosteronism

PRIMARY ALDOSTERONISM:

PRIMARY ALDOSTERONISM Primary Aldosteronism with an Adrenal Tumor Primary Aldosteronism Without an Adrenal Tumor

Primary Aldosteronism with an Adrenal Tumor:

Primary Aldosteronism with an Adrenal Tumor Aldosterone -producing adrenal adenoma (rarely adrenal ca) Also known as Conn's syndrome Usually unilateral M:F : 1:2 Commonly seen between 30-50 yrs ~1% patients present with hypertension

Primary Aldosteronism Without an Adrenal Tumor:

Primary Aldosteronism Without an Adrenal Tumor Idiopathic hyperaldosteronism ,/ nodular hyperplasia The adrenals are either normal in appearance or, more commonly, reveal bilateral(10%) or, rarely, unilateral(<1%) micro- or macronodular adrenal hyperplasia.

CLINICAL FEATURES:

CLINICAL FEATURES Symptoms of hypokalemia like fatigue, loss of stamina, weakness, and lassitude If K + depletion is more severe, increased thirst, polyuria (especially nocturnal), and paresthesias may also be present. Headaches are frequent. Detection of previously unsuspected hypertension during the course of a routine physical examination.

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Hormones of the Adrenal Cortex Slide 9.28b Copyright © 2003 Pearson Education, Inc. publishing as Benjamin Cummings Figure 9.10

Renin-angiotensin-aldosterone axis:

Renin-angiotensin-aldosterone axis Principal factor controlling Ang II levels is renin release. Decreased circulating volume stimulates renin release via: Decreased BP ( symp effects on JGA). Decreased [ NaCl ] at macula densa (“ NaCl sensor”) Decreased renal perfusion pressure (“renal” baroreceptor )

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Pathway of RAAS

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Figure 6.12b

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Atrial natriuretic peptide Decreased blood pressure stimulates renin secretion

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Renin Aldosterone Adrenal cortex Corticosterone Angiotensinogen (Lungs)  renal blood flow &/or  Na + ++ Juxtaglomerular apparatus of kidneys (considered volume receptors) Angiotensin I Converting enzymes Angiotensin II (powerful vasoconstrictor) Angiotensin III (powerful vasoconstrictor) Renin-Angiotensin System: N.B. Aldosterone is the main regulator of Na + retention.

Renin-Angiotension-Aldosterone System:

Renin-Angiotension-Aldosterone System

Na+ Reabsorption:

Na + Reabsorption Angiotensisn II can raise blood pressure by: vasoconstrictor effects. stimulating aldosterone secretion. Insert fig. 17.26

On clinical examinations:

On clinical examinations No characteristic physical findings The mean blood pressure in the 136 patients reported by the Glasgow Hypertension Study unit was 205/123 mm Hg Retinopathy is mild, and hemorrhages are rarely present

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Orthostatic decreases in blood pressure without reflex tachycardia are observed in the severely K + -depleted patient because of blunting of the baroreceptors A positive Trousseau or Chvostek sign may be suggestive of alkalosis accompanying severe K + depletion.

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The heart is usually normal or mildly enlarged ECG changes reflect modest left ventricular hypertrophy and K + depletion Clinical edema is uncommon

DDx of Aldosteronism from Essential Hypertension:

DDx of Aldosteronism from Essential Hypertension Aldo-Producing Adenoma Adrenal Hyperplasia Low-renin essential HTN Age Middle-aged Older Older Hypokalemia Frequent Less common Uncommon Plasma renin levels Very low Low Low Plasma aldo levels Very high High-normal Normal Plasma aldo suppressibility to volume Minimal Partial Complete

The criteria for the diagnosis of primary aldosteronism :

The criteria for the diagnosis of primary aldosteronism Diastolic hypertension without edema Hyposecretion of renin (as judged by low plasma renin activity levels) that fails to increase appropriately during volume depletion (upright posture, sodium depletion) Hypersecretion of aldosterone that does not suppress appropriately in response to volume expansion

Diagnosis:

Diagnosis Aldosterone >15 ng / dL Aldo / Renin ratio >30 Confirmation w/ Na+ suppression test Imaging of the adrenal glands Adrenal Vein Sampling (AVS) 18-OH Corticosterone levels may help differentiate between hyperplasia and adenoma > 100 think adenoma <60 think consistent w/ hyperplasia

Imaging:

Imaging CT and MRI both considered reasonable ? Carcinoma if adrenal mass >4cm Bilateral abnormalities, ie . micronodular appearance, suggests hyperplasia People w/ adrenal mass may still have bilateral hyperplasia Absence of a mass does not exclude <1cm adenomas

Adrenal Vein sampling:

Adrenal Vein sampling Considered gold std. to distinguish between adenoma and hyperplasia Usually done under ACTH infusion Looking for localization of aldosterone increase Very useful when no abnormalities seen on imaging or bilateral nodules

Tests Confirming the Diagnosis of Primary Aldosteronism:

Tests Confirming the Diagnosis of Primary Aldosteronism Suppressed Upright Renin < 1 ng /ml/h Plasma supine aldosterone at 0800h > 15 ng /dl Urinary aldosterone metabolites 18-Monoglucuronide > 20 ug /24h Tetrahydroaldosterone > 65 ug /24h NaCl infusion/ suppression test -- PA > 10 ng /dl ACE inhibition test captopril test -- PA > 15 ng /dl

Aldosterone Suppression Tests:

Aldosterone Suppression Tests IV Saline suppression 500 mL 0.9% NaCl/hr for four hours OR 500 mL 0.9% NaCl over 30 minutes, then 500 mL /hr for 2 hours (1.5 liters over 2.5 hours) Draw PAC at time 0, 120, 150 minutes for short test Suppression if PAC <8.5 ng / dL (<6 normal >10 PA) Oral sodium chloride suppression test 10 gms NaCl daily for 4 days On day 4, collect 24 hour urine aldosterone, sodium Suppression if aldosterone<14 mcg and sodium > 200 mEq /24 hours Fludrocortisones suppression test high salt diet and large doses of Florinef over a 4 day hospitalization %ARR with lack of suppression – mean 60% , range 26-95% (Kaplan NM, J Hypertension 22:863-69, 2004)

When to Screen?:

When to Screen? Recommended in hypertensive pt with one of the following: hypokalemia severe, resistant, or relatively acute HTN adrenal incidentaloma

Method of screening:

Method of screening Aldosterone conc. / Renin activity ratio Considered positive if ratio >20, usually > 30 In addition, the Aldo conc. should be >15 ng / dL Aldo >20 & ratio >30 had sens. /spec. = 90% Retrospective study from 5 continents used a ratio range of 20- 40 as (+).

3 scenarios:

3 scenarios ↑ renin , ↑ aldosterone (ratio <10) – Secondary ↓ renin , ↑ aldosterone (ratio >20) – Primary ↓ renin , ↓ aldosterone – mineralcorticoid excess, ie . non-aldosterone

Management:

Management Goals: Normalize BP Decrease/eliminate the deleterious effects of increased aldosterone on the heart & kidney Pt’s w/ primary hyperaldo are more likely to have: LVH, stroke, and MI than other hypertensive pts. ? Mediated by mineralcorticoid receptors in cardiac tissue. Increased urine albumin excretion compared to other hypertensive pts

Management:

Management Adenoma/Carcinoma Call surgery Use spironolactone pre-operatively to correct hypoK + Hyperplasia Spironolactone – drug of choice (max 200mg/day) Eplerenone – newer, more $$, fewer side-effects Amiloride & triamterene don’t protect the heart

Secondary Aldosteronism:

Secondary Aldosteronism Increased production of aldosterone in response to activation of the renin-angiotensin system The production rate of aldosterone is often higher in patients with secondary aldosteronism than in those with primary aldosteronism

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Secondary aldosteronism in pregnancy is a normal physiologic response to estrogen-induced increases in circulating levels of renin substrate and plasma renin activity and to the antialdosterone actions of progestogens . primary overproduction of renin (primary reninism ) Overproduction of renin secondary to a decrease in renal blood flow and/or perfusion pressure

causes:

causes Narrowing of renal arteries 1. Atherosclerosis 2. Fibromusclar dysplasia Severe arteriolar nephrosclerosis (malignant hypertension) Profound renal vasoconstriction (the accelerated phase of hypertension)

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Cirrhosis of liver Nephrotic syndrome Congestive cardiac failure Drugs like furesmide,thiazides as these causes volume depletion

Secondary Aldosteronism:

Secondary Aldosteronism Characterized by 1. hypokalemic alkalosis 2. moderate to severe increases in plasma renin activity 3. moderate to marked increases in aldosterone levels

Liddle's Syndrome :

Liddle's Syndrome In 1963, Liddle and colleagues reported this with clinical manifestations resembling those of classic primary aldosteronism : 1. hypertension, 2. hypokalemia with renal K + wasting, 3. metabolic alkalosis, and 4. suppressed plasma renin activity The inheritance pattern was autosomal dominant disorder,

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Primary abnormality in the renal tubule that enhanced Na + reabsorption was responsible Liddle's syndrome have a defect in the cytoplasmic domain of either the or subunit of the epithelial Na + channel that results in constitutive activation of the channel Amiloride,Triamterene are specific inhibitors of this channel, treatment with these agents corrects the electrolyte abnormalities and ameliorates the hypertension as well.

Hypoaldosteronism :

Hypoaldosteronism Hyporeninemic hypoaldosteronism Hyperreninemic hypoaldosteronism

Hyporeninemic hypoaldosteronism :

Hyporeninemic hypoaldosteronism Isolated aldosterone deficiency with normal cortisol production Hyporeninism Inherited biosynthetic defect, Postoperatively following removal of aldosterone-secreting adenomas In pretectal disease of the nervous system, and in severe postural hypotension.

pathogensis:

pathogensis Autonomic neuropathy ECFV expansion Defective conversion of renin precursors to active renin .

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most commonly seen in adults with 1. diabetes mellitus 2. mild renal failure 3. hyperkalemia and 4. metabolic acidosis are out of proportion to the degree of renal impairment. Plasma renin levels fail to rise normally following sodium restriction and postural changes.

Hyperreninemic hypoaldosteronism :

Hyperreninemic hypoaldosteronism high renin levels and low or elevated levels of aldosterone high mortality rate (80%). Hyperkalemia is not present. Hypoaldosteronism due to adrenal necrosis (uncommon) or a shift in steroidogenesis from mineralocorticoids to glucocorticoids , possibly related to prolonged ACTH stimulation.

management:

management Low renin and aldosterone levels establish the diagnosis of hyporeninemic hypoaldosteronism high renin levels and low aldosterone levels is consistent with an aldosterone biosynthetic defect or a selective unresponsiveness to angiotensin II.

treatment:

treatment To replace the mineralocorticoid deficiency 0.05–0.15 mg fludrocortisone PO daily Hyporeninemic hypoaldosteronism may require higher doses of mineralocorticoid to correct hyperkalemia An alternative approach is to reduce salt intake and to administer furosemide , which can ameliorate acidosis and hyperkalemia

ALDOSTERONE ANTAGONIST:

ALDOSTERONE ANTAGONIST These are potassium sparing diuretic Antagonize the effects of aldosterone at the late distal tubule and cortical collecting tubule Direct pharmacologic antagonism of mineralocorticoid receptors These are 1. Spironolactone 2. Eplerenone

Pharmacokinetics :

Pharmacokinetics Spironolactone is a synthetic steroid that acts as a competitive antagonist to aldosterone Metabolized in liver to active metabolite Canrenone with t ½ 18 hrs slow onset of action Eplerenone, a new spironolactone analog with greater selectivity for the aldosterone receptor

uses:

uses Edema Hypertension Congestive heart failure To counteract K+ loss due to thiazide and loop diuretics

Drug interactions:

Drug interactions Dangerous hyperkalemia with K+ supplements Aspirin blocks spironolactone action by inhibiting tubular secretion of canrenone Hyperkalemia with ACE inhibitors/ARBs Spironolactone increases plasma digoxin concentration

Toxicity/adverse effects:

Toxicity/adverse effects Hyperkalemia Hyperchloremic Metabolic Acidosis Gynecomastia Hirsutism,impotence & menstrual irregularities

eplerenone:

eplerenone Newer more selective aldosteronre antagonist Less likely to cause hormonal distrubances like gynaecomastia,impotence & menstrual irregularities Used in CHF patients

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Aldosterone Antagonist: Mechanism of Action Aldosterone Sodium and Water Retention Edema Potassium and Magnesium Excretion Arrhythmias Collagen deposition Myocardial and Vascular Fibrosis

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Pitt B et al. NEJM 1999;341:709-717 RR = 0.70, P<0.001 Months Survival (%) 36 33 30 27 24 21 18 15 12 9 6 3 0 1.00 .90 .80 .70 .60 .50 0 Aldosterone Antagonist: Secondary Prevention Randomized Aldactone Evaluation Study (RALES) EF=Ejection fraction, HF=Heart failure, LVSD=Left ventricular systolic dysfunction, NYHA=New York Heart Association Spironolactone Placebo 1,663 patients with NYHA Class III or IV HF and LVSD (EF <0.35) randomized to spironolactone (25-50mg) or placebo for 24 months Aldosterone inhibition reduces death in patients with advanced heart failure

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RR = 0.85, P=0.008 6 12 18 24 30 36 0 5 10 15 20 25 0 All Cause Mortality (%) Month Aldosterone Antagonist: Secondary Prevention Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) Eplerenone Placebo 3,313 patients with evidence of HF and LVSD (EF <0.40) after a MI randomized to eplerenone (25-50 mg) or placebo for 16 months Aldosterone inhibition improves survival in patients with post-MI HF and LVSD Pitt B et al. NEJM 2003;348:1309-21 EF=Ejection fraction, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction, HF=Heart failure

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Aldosterone Antagonist: Guidelines Aldosterone antagonist in UA/NSTEMI patients already receiving and ACE-I with LVSD (EF <0.40) and either symptomatic HF or DM Aldosterone antagonist in those with LVSD (EF<0.35) and recent or current NYHA class IV HF symptoms* Secondary Prevention ACE-I=Angiotensin converting enzyme inhibitor, DM=Diabetes mellitus, EF=Ejection fraction, HF=Heart failure, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction, NYHA=New York Heart Association *Contraindications include abnormal renal function (creatinine > 2.5 mg/dL in men or > 2.0 mg/dL in women) and hyperkalemia (K+ > 5.0 meq/L)

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