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Flashcards in Adrenal Pharmacology Deck (40):
1

Classification of Adrenal Corticosteroids

a. Glucocorticoids. Principally involved in carbohydrate and protein metabolism and anti-inflammatory response. Cortisol is prototype hormone.

b. Mineralocorticoids. Principally involved in Na+ retention.
i. Aldosterone is prototype hormone.

c. Adrenal Androgens.
i. Increased release occurs in concert with cortisol, but not aldosterone.

d. Dihydroandrostenedione (DHEA) and androstenedione have weak androgenic activity, but some DHEA is converted to testosterone and estradiol outside of the adrenal gland.

2

Regulation of Secretion and Synthesis of Adrenal Corticosteroids

a. Pituitary adrenocorticotropic hormone (ACTH) release is controlled by corticotropin-releasing factor (CRF) from the hypothalamus.
i. Synthesis and secretion of glucocorticoids and androgens is controlled by actions of ACTH at the adrenal cortex.

NOTE: The renin-angiotensin system is the primary regulator of mineralocorticoid (aldosterone) synthesis and release.

b. Glucocorticoid pathway is a substrate-limited system with synthetic enzymes in excess that provides for rapid responsiveness.
i. Rate-limiting step is conversion of cholesterol to pregnenolone.
ii. ACTH stimulates this step and at several levels in zona fasiculata and in the zona reticularis (androgens).
iii. Synthesis is inhibited by metyrapone and mitotane (also inhibited by ketoconazole).

c. Mineralocorticoid pathway in zona glomerulosa has 18-OH-steroid dehydrogenase enzyme that converts corticosterone to aldosterone.
i. Renin-angiotensin system (via angiotensin II) stimulates conversion of cholesterol to pregnenolone and corticosterone to aldosterone (independent of ACTH).

3

Physiologic Actions - Glucocorticoids
Mechanism of action:

Most actions mediated by widely distributed glucocorticoid receptors

1. Steroid [S] binds to intracellular receptors [R] in cytosol

2. Forms [S-R] complex that is transported to nucleus

3. Binds to Glucocorticoid Response Element [GRE] on DNA
[plus other transcription factors that regulate growth factors and proinflammatory cytokines]

4. Activates or inhibits transcription of target genes increase or decrease in protein synthesis

5. Alteration of cellular function – onset of effects in hours or more

4

Metabolic effects (physiologic levels of Glucocorticoids)

a. Carbohydrate: Stimulate gluconeogenesis (in fasting state) increased blood glucose (leading to---> insulin release).
i. Stimulates gluconeogenesis and glycogen synthase activity increased liver glycogen deposition. [In excess, can lead to diabetes-like state.]

b. Protein: Increase AA uptake into liver and kidney, decreased protein synthesis (except liver) net transfer of AA from muscle / bone to liver (into glucose).
i. [In excess, can lead to muscle wasting, while catabolic effects in skin and connective tissue result in atrophy.]

c. Lipid: Inhibit uptake of glucose by fat cells stimulate lipolysis (but net effect is lipogenesis due to increased insulin release).
i. Greater lipogenic effect in central tissues. [In excess, can see as centripetal obesity (buffalo hump, increased abdominal fat).]

d. Net Physiologic Result: Maintenance of glucose supply to brain (insulin antagonism)

5

Physiologic Actions - Mineralocorticoids

a. Mechanism of Action: Aldosterone binds to cytosolic receptor that migrates to nucleus where it induces formation of mRNA to direct synthesis of specific proteins (Na+-K+-ATPase, Na+ and K+ channels)

b. Insertion of protein in membrane induces increased reabsorption of Na+ from renal distal tubules that is loosely coupled to increased secretion of H+ and K+.

6

Pharmacology of Glucocorticoids and Mineralocorticoids

a, Structure Activity Relationships. All natural steroids have both glucocorticoid (GCC) and mineralocorticoid (MCC) activity, except 11-deoxycorticosterone.

b. Intensive investigation of synthetic analogs has demonstrated that GCC and MCC effects can be separated but NOTE that metabolic (GCC) effects can NOT be separated from anti-inflammatory effects and anti-inflammatory effects can NOT be separated from immunosuppressive effects.

c. Changes in structure can also be made that affect specificity, potency, absorption, protein binding, rate of metabolism/excretion, membrane permeability

7

Effects of Selected Structural Modifications

in Glucocorticoids and Mineralocorticoids

a. Hydroxyl group (−OH) at the 11 position: Necessary for intrinsic glucocorticoid activity

b, Carbonyl group (=O) at the 11 carbon: Compounds are inactive until liver enzyme 11-hydroxysteroid dehydrogenase type I (11Beta-HSD I) reduces compound to 11-hydroxyl congener.
i. NOTE: Skin does not have this enzyme, thus drugs in Panel B cannot be used in topical glucocorticoid preparations.

c. Double bond between C-1 and C-2: Increases anti-inflammatory effects 4-5 fold (prednisolone vs cortisol).

d. Addition of alpha-methyl group to carbon 6: Increases anti-inflammatory effects 5-6 fold (methylprednisolone vs cortisol).

e. Addition of fluorine to C-9: Enhances glucocorticoid and especially mineralocorticoid activity. Fludrocortisone is the drug of choice for mineralocorticoid effects.

f. Addition of fluorine to C-9 plus addition of alpha-methyl group on C-16: Increases anti-inflammatory effects 18 fold and essentially eliminates mineralocorticoid activity (dexamethasone vs cortisol).

8

Metabolism: What Affects Duration of Action and Effectiveness?

Pharmacology of Glucocorticoids and Mineralocorticoids

a. Liver inactivates by reduction of double bonds and conjugation to glucuronic acid, makes cortisol more water soluble.
i. Two forms of major metabolic enzyme - 11Beta-hydroxysteroid dehydrogenase (11BetaHSD)
1. Liver: 11Beta-HSD1 converts cortisone back to cortisol (or prednisone to prednisolone) – activating step.

2. Kidney: 11Beta-HSD2 converts cortisol to cortisone - inactivating step (“protects” kidney from MC activity of cortisol).

3. Fetus: Placental 11-HSD2 (inactivating form) is active, but not 11HSD1 as fetal liver is not functional.

Can treat mother with glucocorticoids without effect on fetus because placental enzyme can convert active drug back to prodrug (e.g., prednisolone to prednisone).

b. Plasma Protein Binding via corticosteroid binding globulin (CBG) and albumin. 90% of circulating cortisol is bound, only unbound is bioavailable (able to diffuse into cells). Most analogs bind to CBG with low affinity, approximately 2/3 binds to albumin, rest is free (free is metabolized).

c. Increased Lipophilicity: promotes partitioning into adipose tissue, extending half-life.

9

Clinical Use of Adrenocorticosteroid Agents

Mineralocorticoid versus Glucocorticoid Activity

a. Mineralocorticoid activity refers to salt (Na+)-retaining actions at the kidney. Glucocorticoid activity refers to metabolic effects (hyperglycemia, protein wasting, lipid redistribution).
i. Since it is not possible to design a molecule that has anti-inflammatory activity without glucocorticoid activity, these activities are interchangeable


b. The natural glucocorticoid molecule, cortisol (aka hydrocortisone), possesses equal amounts of glucocorticoid and mineralocorticoid activity.
i. The natural mineralocorticoid molecule, aldosterone, possesses essentially all mineralocorticoid activity.

c. Fludrocortisone, a longer-acting analog of aldosterone is used in replacement therapy for adrenocortical insufficiency; used at dosages sufficient for salt-retaining activity without glucocorticoid or anti-inflammatory activity.

10

Physiologic versus Pharmacologic Uses

a. When using these agents in physiologic replacement regimens (e.g., Addison’s disease), it is necessary to use an agent with both glucocorticoid and mineralocorticoid activity such as cortisol.
i. Agents such as dexamethasone or triamcinolone would be inappropriate.

b. When using these agents in pharmacologic doses for their anti-inflammatory or immunosuppressive actions, it is desirable to select an agent with minimal or no mineralocorticoid activity (e.g., dexamethasone).
i. Ideally, one would desire to also select an anti-inflammatory steroid without glucocorticoid activity, but that is not possible at the present time.
ii. Thus, any time these adrenocorticosteroids are used to treat inflammatory conditions, the possibility of glucocorticoid metabolic side effects must be considered.

11

Adrenocortical Insufficiency

Physiologic replacement therapy in chronic or acute conditions

a. Chronic (Addison's disease): 20-30 mg/day cortisol (often 15-20 mg AM, 5-10 mg PM).
i. Dose should be increased dose by 2-4 fold during periods of stress.
ii. Unless mild disease, fludrocortisone is usually required for sufficient salt-retaining effect.
iii. DHEA may have benefits in some patients.

b. Acute: Life-threatening, so immediate treatment needed.
i. Large amounts IV cortisol (100 mg q 6-8 hrs) until stable; must correct fluid/electrolyte abnormalities.
ii. Fludrocortisone may be required in some patients after switch to lower oral maintenance doses of cortisol (hydrocortisone).

12

Adrenocortical Hyperfunction: Cushing's Syndrome (Hypercortisolism)

a. Causes
i. Pituitary tumor secreting excess ACTH [70%] (Cushing’s Disease)
ii. Non-pituitary (ectopic) tumor secreting excess ACTH [15%]
iii. Adrenal tumor secreting excess cortisol [15%]

b. Surgery is treatment of choice

c. Pharmacotherapy - generally reserved for adjunctive therapy in refractory or inoperable cases

d. Glucocorticoid synthesis inhibitors: Divided into agents affecting early (broad effects) or later (more specific effects) steps in steroid biosynthesis.
Early: Ketoconazole

13

Adrenocortical Hyperfunction: Congenital Adrenal Hyperplasia

a. Cortisol synthesis and secretion is diminished because of congenital enzyme defects in biosynthetic pathway resulting in increased ACTH and adrenal hyperplasia (due to lack of cortisol to suppress ACTH secretion, thus overstimulation of adrenal gland).
i. Can be accompanied by excess or deficient levels of adrenal mineralocorticoids and androgens.

1. 21-hydroxylase deficiency
i. No cortisol synthesis---> Increased ACTH --> allowing excess androgens--> virilizing
ii. No desoxycorticosterone OR aldosterone synthesis --> decrease Mineralcorticoid activity---> hypotension

2. 17α-hydroxylase deficiency
i. No adrenal androgen synthesis-->non-virilizing
ii. No cortisol synthesis--> increaseACTH --> increase desoxycorticosterone --> increase MC activity --> hypertension

3. 11Beta-hydroxylase deficiency
i. No cortisol synthesis--> increased ACTH ---> allowing excess androgens ---> virilizing
ii. No cortisol synthesis--> increase ACTH ---> increase desoxycorticosterone--> increase MC activity-->hypertension
iiii. NOTE: desoxycorticosterone possesses considerable MC activity (see previous table)

b. The goal of therapy is to replace deficient steroids while minimizing adrenal sex hormone (overproduction) and glucocorticoid excess (via overtreatment). Hydrocortisone is used in children while longer acting agents (prednisone or dexamethasone) are preferred in adults. Fludrocortisone can be used if mineralocorticoid replacement is necessary.

14

Adrenocortical Hyperfunction: Pheochromocytoma

a. The signs and symptoms of pheochromocytoma are related to the pathophysiology of excess catecholamine secretion.
i. Treatment is achieved by surgical removal of the tumor after appropriate pre-operative alpha-adrenergic receptor blockade to avoid a hypertensive crisis during surgery.

b. Pharmacologic Preparation for Surgery. Aimed at controlling hypertension along with volume expansion to counter catecholamine-induced volume contraction.
1. Phenoxybenzamine, an irreversible α1-α2 receptor antagonist, is given twice daily with upward dose titration every 3 days until blood pressure controlled

2. Beta-blockade (e.g., metoprolol) - after adequate alpha-adrenergic receptor blockade has been achieved - can be employed 2-3 days preoperatively to control tachycardia and other arrhythmias.

NOTE: Block of beta-2 receptors (i.e., block of beta-2 mediated vasodilation) with non-selective beta blockers (e.g., propranolol [1-2] or labetalol [α1-1-2]) prior to alpha-1 block may result in severe hypertension due to effects of epinephrine on alpha-1 receptors mediating unopposed vasoconstriction.

3. Calcium channel blockers (nifedipine) can be used to supplement alpha- and beta-blockade if blood pressure control is inadequate or side effects of alpha-blockade with phenoxybenzamine are not tolerated

15

Pharmacologic Applications of Hormones

Diagnostic tools: Test for site of disorder along axis in hypo- or hyperfunctional endocrine states

Management of hypofunction: Hormone replacement (physiologic) therapy for deficiency states

Management of hyperfunction: Suppression of hormone synthesis or effect (nonhormonal agents)

Alteration of normal endocrine states: Interference with normal function in order to achieve desired state

Control of non-endocrine disorders: Drug therapy for variety of diseases using pharmacologic doses
[Presented in DandD for glucocorticoids]

16

Clinical Uses
Physiologic vs Pharmacologic Doses

a. Physiologic replacement regimens (Addison’s disease)
i. Use an agent with both glucocorticoid and mineralocorticoid activity such as cortisol or add fludrocortisone (MC)

b. Pharmacologic doses for anti-inflammatory or immuno-suppressive actions
i. Desirable to select an agent with minimal or no mineralo-corticoid activity (e.g., dexamethasone)
ii. Not possible to avoid GC metabolic side effects with the anti-inflammatory GCs currently available

17

Glucocorticoid Metabolic Effects – Cortisol

Physiologic vs Pharmacologic Doses

a. Carbohydrate: Increased gluconeogenesis blood glucose ( insulin)
i. Excess---> hyperglycemia (diabetes-like state)

b. Protein: decreased--> increased protein synthesis AA to glucose
i. Excess---> muscle wasting, skin-connective tissue atrophy

c. Fat: Increased lipolysis (peripherally)--> increased free fatty acids
i. Excess --> Increased lipogenesis (centrally via insulin action)---> centripetal obesity (moon facies, buffalo hump)

18

Mineralocorticoid Effects – Aldosterone

Physiologic vs Pharmacologic Doses

a. Increased Na+ reabsorption at kidney---> increased blood volume and BP (loosely coupled to K+ and H+ secretion)

b. Excess---> fluid retention, hypertension, hypokalemia


NOTE: GC Effects can be separated from MC Effects

BUT: Cannot Separate GC Metabolic Side Effects from
A-I and I-S Therapeutic Effects

19

Adrenal Insufficiency : Treatment

*Other lecture notes

a. Glucocorticoid Replacement (Primary + Secondary)
i. Hydrocortisone = Cortisol: 15-25 mg/day
ii. Prednisone: 4-5 mg/day
iii. Dexamethasone: 0.75-1.0 mg/day

b. Mineralocorticoid Replacement (Primary Only[?])
i. Fludrocortisone: 0.05-0.1 mg/day

c. Sex Steroid Replacement (Women)
i. DHEA**: 25-50 mg/day (dietary supplement)

20

Metabolism of Glucocorticoids

11-hydroxysteroid dehydrogenase (11HSD)

a. Liver: 11 Beta-HSD1 can convert prednisone to prednisolone – activating

b. Kidney: 11 Beta-HSD2 converts cortisol back to cortisone - inactivating (less MC activity at kidney)

c. Fetus: 11 Beta-HSD2 protects fetus from effects of maternal steroids (cortisol back to cortisone)

21

Clinical Pharmacology – Adrenal Disorders

Adrenocortical Insufficiency

a. Chronic (Addison's disease) Treatment
1. Oral hydrocortisone: 15-25 mg/day in 2-3 divided doses - roughly mimics the normal diurnal rhythm

2. Long-acting agents provide smoother physiologic effect given daily (dexamethasone - prednisone)

3. Temporary dosage increase necessary with illness (3x3) or surgery (graded based on severity)

4. Fludrocortisone can be added to therapy if additional salt-retaining activity is needed (if patient hypotensive)

5. DHEA (dehydroepiandrosterone) supplementation may be needed in some women (mood and well-being)

b. Acute--> adrenal crisis: electrolyte abnormalities (Decreased Na+ and Increased K+) and plasma volume depletion
i. Volume replenishment with NS or D5NS

ii. If previous diagnosis: large amounts IV hydrocortisone (100 mg q 6-8 hrs)

iii. Without previous diagnosis: dexamethasone (not measured in serum cortisol assays)

iv. Additional MC action > hydrocortisone not needed acutely unless hyperkalemia present (K+ > 6.0 meq/L)

22

Adrenocortical Insufficiency

Acute--> adrenal crisis: electrolyte abnormalities (Decreased Na+ and Increased K+) and plasma volume depletion

1. Volume replenishment with NS or D5NS

2. If previous diagnosis: large amounts IV hydrocortisone (100 mg q 6-8 hrs)

3. Without previous diagnosis: dexamethasone (not measured in serum cortisol assays)

4. Additional MC action > hydrocortisone not needed acutely unless hyperkalemia present (K+ > 6.0 meq/L)

23

Chronic (Addison's disease) Treatment

Adrenocortical Insufficiency

1. Oral hydrocortisone: 15-25 mg/day in 2-3 divided doses - roughly mimics the normal diurnal rhythm
* know this

2. Long-acting agents provide smoother physiologic effect given daily (dexamethasone - prednisone)
*know this

3. Temporary dosage increase necessary with illness (3x3) or surgery (graded based on severity)

4. Fludrocortisone can be added to therapy if additional salt-retaining activity is needed (if patient hypotensive)
* know this

5. DHEA (dehydroepiandrosterone) supplementation may be needed in some women (mood and well-being)
*know this

24

Cushing’s Syndrome
Treatment

*other lecture

a. Surgery: Pituitary, Chest, Abdomen

b. Pharm Tx
1. ACTH Secretion Inhibitors:
Cabergoline [D2 agonist] - Pasireotide [SST analog]

2. Cortisol Synthesis Inhibitors:
i. Ketoconazole, Metyrapone, Etomidate

3. Adrenolytic Agents:
Mitotane

4. Cortisol Receptor Blockers:
Mifepristone

25

Adrenocortical Hyperfunction
Cushing's Syndrome (Hypercortisolism)

Treatment

a. Surgery is treatment of choice

b. Pharmacotherapy: generally reserved for adjunctive therapy in refractory or inoperable cases, can include:

c. Synthesis inhibitors: Divided into agents affecting early (broad effects) or later (more specific effects) steps in steroid biosynthesis
i. Early
Mitotane
Ketoconazole
Aminoglutethimide
Trilostane
ii. Late
Metyrapone

d. Glucocorticoid receptor antagonist: Mifepristone (RU-486)

26

Adrenal Enzyme Inhibitors

1. Ketoconazole
i. Most commonly used - higher dose than antifungal use; also inhibits C17-20 desmolase (decrease testosterone synthesis)
ii. ADRs: headache, n/v, gynecomastia-impotence, reversible hepatotoxicity

2. Metyrapone
i. Lesser used (mild disease) - add on to ketoconazole; inhibits 11β-hydroxylase - can increase adrenal androgen production
ii. ADRs: increase hirsutism in women, Na+ retention and hypertension (increase in DOCA synthesis)

27

Ketoconazole

a. Treatment in Cushing's Syndrome (Hyper adrenocorticol function)

b. Most commonly used - higher dose than antifungal use; also inhibits C17-20 desmolase (decrease testosterone synthesis)

c. ADRs: headache, n/v, gynecomastia-impotence, reversible hepatotoxicity

28

Metyrapone

a. Used for TX of Treatment in Cushing's Syndrome (Hyper adrenocorticol function)

b. Lesser used (mild disease) - add on to ketoconazole; inhibits 11β-hydroxylase - can increase adrenal androgen production

c. ADRs: increase hirsutism in women, Na+ retention and hypertension (increase in DOCA synthesis)

29

Mifepristone

Approved in 2012 to control hyperglycemia secondary to Cushing’s syndrome - Orphan Drug

Mifepristone is used for the medical treatment of high blood sugar (hyperglycemia) caused by high cortisol levels in the blood (hypercortisolism) in adults with endogenous Cushing’s syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or cannot have surgery

Also used for abortions

30

Primary Aldosteronism

a. Primary aldosteronism, also known as primary hyperaldosteronism or Conn's syndrome, is excess production of the hormone aldosterone by the adrenal glands resulting in low renin levels.
i. Often it produces few symptoms.

b. Most people have high blood pressure which may cause poor vision or headaches.
i. Occasionally there may be muscular weakness, muscle spasms, tingling sensations, or excessive urination.[1]

c. Complications include cardiovascular disease such as stroke, myocardial infarction, kidney failure, and abnormal heart rhythms.

31

Calcium Channel Blockers
Selectivity for Vascular vs Heart Ca++ Channels

a. Dihydropyridines (nifedipine) have greater ratio of vascular (dilation) to cardiac (rate-conduction-contractility) effects

b. Verapamil and diltiazem, each at a distinct site, also have prominent effects at cardiac nodal tissue (phase 0 at SA and AV node) and on cardiac muscle (phase 2)

32

Adrenocortical Hyperfunction
Pheochromocytoma

Treatment

a. Surgery is treatment of choice

b. Pharmacologic Preparation for Surgery

1. Phenoxybenzamine: irreversible α1-α2 receptor antagonist OR Terazosin-Doxazosin: reversible α1 receptor antagonist

2. Metoprolol: -1 blocker following alpha blockade OR Labetalol: α1-β1-β2 blocker

3. Nicardipine: calcium channel blocker--->if BP control inadequate

4. Metyrosine: catecholamine synthesis inhibitor-->if inoperable or metastatic
i. Inhibits rate-limiting enzyme for NE-Epi biosynthesis - tyrosine hydroxylase

33

Pharmacology of Glucocorticoids

a. Anti-Inflammatory - Immunosuppressive Effects
1. Effects on vascular events reduced--> vasodilation, decreased fluid exudation

2. Effects on cellular events---> decrease in accumulation and activation of inflammatory and immune cells

3. Effects on inflammatory and immune mediators decrease in synthesis

b. Upside: GCs suppress chronic inflammation and autoimmune reactions

c. Downside: GCs also decrease healing and diminish immunoprotection

34

Dosing Considerations for Anti-Inflammatory Use

a. REMEMBER: Mineralocorticoid side effects vary with agent

b. Dosage often by trial and error with re-evaluation

c. Consider seriousness of disease - minimal amount for desired effect - duration of therapy

d. Reduce dosage as soon as therapeutic objectives are obtained

35

Clinical Use of Adrenocorticoids

(list of different Adrenocorticoids)

Agents:

1. Primary Glucocorticoid Cortisol
i. Anti-inflammatory effect: 1
ii. MC (salt retaining): 1
*average topical

2. Prednisone:
i. Anti-inflammatory effect: 4
ii. MC (salt retaining): .3
*No topical

3. Dexamethasone:
i. Anti-inflammatory effect: 30
ii. MC (salt retaining): 0
*High Topical

4. Fludrocortisone
i. Anti-inflammatory effect: 10
ii. MC (salt retaining): 125-250
*No topical

36

Treatment of Acute Adrenocortical Insuffuciency

Acute--> adrenal crisis: electrolyte abnormalities (Decreased Na+ and Increased K+) and plasma volume depletion
-can have life threatening arrhythmias

a. Volume replenishment with NS or D5NS

b. If previous diagnosis: large amounts IV hydrocortisone (100 mg q 6-8 hrs)
*know this

c. Without previous diagnosis: dexamethasone (not measured in serum cortisol assays)
*know this

d. Additional MC action > hydrocortisone not needed acutely unless hyperkalemia present (K+ > 6.0 meq/L)

37

Primary Aldosteronism
Treatment - APA (adenoma)

a. Pre-Operative: Aldosterone Antagonists--> block the high aldosterone
i. Spironolactone
ii. Eplerenone


then...

b. Adrenalectomy
Laparoscopic / Open
i. remove the tumor

38

Primary Aldosteronism
Treatment - IHA - Medical

Goals: Normalization of hypokalemia and blood pressure


1. Aldosterone Antagonists (K+ sparing)
i. Spironolactone
ii. Eplerenone

2. BP Medications
i. Calcium channel blocks
ii. Ace inhibitors
iii. ARBs

39

PheochromocytomaPreoperative Management

*know these (don't memorize dose)

1. Alpha Blockers (1st)
Phenoxybenzamine: 20-100 mg qd
Prazosin: 1-5 mg BID
Terazosin: 2-10 mg QD
Doxazosin: 1-16 mg QD

2. Beta Blockers (2nd – after Alpha Blockade)

3. Calcium Channel Blockers (alone)

40

Pheochromocytoma Treatment

a. Pre-Operative
Alpha blocker (1st)
Beta blocker (2nd)
or
Calcium channel blocker

b. Rx Effects:
i. Vasodilation--> via block of α1
ii. Volume Expansion
iii. Rate Control-->via block of β1


Then.... (after pre-operative drugs)

c. Adrenalectomy
Laparoscopic
Open