Adrenal Pharmacology Flashcards
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.
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).
Physiologic Actions - Glucocorticoids
Mechanism of action:
Most actions mediated by widely distributed glucocorticoid receptors
- Steroid [S] binds to intracellular receptors [R] in cytosol
- Forms [S-R] complex that is transported to nucleus
- Binds to Glucocorticoid Response Element [GRE] on DNA
[plus other transcription factors that regulate growth factors and proinflammatory cytokines] - Activates or inhibits transcription of target genes increase or decrease in protein synthesis
- Alteration of cellular function – onset of effects in hours or more
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)
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+.
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
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).
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.
- Kidney: 11Beta-HSD2 converts cortisol to cortisone - inactivating step (“protects” kidney from MC activity of cortisol).
- Fetus: Placental 11-HSD2 (inactivating form) is active, but not 11HSD1 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.
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.
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.
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).
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
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.
- 21-hydroxylase deficiency
i. No cortisol synthesis—> Increased ACTH –> allowing excess androgens–> virilizing
ii. No desoxycorticosterone OR aldosterone synthesis –> decrease Mineralcorticoid activity—> hypotension - 17α-hydroxylase deficiency
i. No adrenal androgen synthesis–>non-virilizing
ii. No cortisol synthesis–> increaseACTH –> increase desoxycorticosterone –> increase MC activity –> hypertension - 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.
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
- 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.
- 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
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]
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
