Pharmacology of Adrenal Cortex (II) PDF

Pharmacology of adrenal cortex (II) Gabriela Cristina Brailoiu, MD  Objectives 1. Discuss routes of administration of glucocorticoids and the benefits of local administration 2. Discuss the inhibitors of corticosteroids synthesis and receptor antagonists 3. Discuss the physiology and pharmaco...

Pharmacology of adrenal cortex (II) Gabriela Cristina Brailoiu, MD  Objectives 1. Discuss routes of administration of glucocorticoids and the benefits of local administration 2. Discuss the inhibitors of corticosteroids synthesis and receptor antagonists 3. Discuss the physiology and pharmacology of mineralocorticoids 4. Discuss the physiology and pharmacology of adrenal androgens  Glucocorticoids Routes of Administration Oral (tablet, solution, syrup) Parenteral (IV, IM, intra-articular injection) Topical (lotion, cream, gel, ointment) Inhaled (aerosol) Ophthalmic, otic (solution, ointment) Objective 1  Glucocorticoids Routes of Administration – inhalation Inhaled glucocorticoids Drugs: – Fluticasone, Beclomethasone, Flunisolide, Ciclesonide, Budesonide, Mometasone Indications: – chronic treatment of asthma – oral inhalation -formulation of choice In combination therapy with Long-Acting Beta2 -Agonists (LABA): Salmeterol + Fluticasone (Advair ®) Formoterol + Budesonide (Symbicort ®) Adverse effects: – oropharyngeal candidiasis Objective 1  Glucocorticoids Routes of Administration – topical Topical (cutaneous) glucocorticoids Must be biologically active (skin lacks 11β-HSD1 enzyme) Drugs: – Hydrocortisone, Methylprednisolone, Dexamethasone – not Prednisone Indications: – atopic dermatitis, psoriasis Objective 1  Topical Corticosteroids – Relative Potency Very High Potency Steroid Dosage form 0.05% Betamethasone dipropionate, augmented Gel, lotion, ointment 0.05% Clobetasol propionate Cream, foam, gel, lotion, ointment, shampoo, spray 0.05% Diflorasone diacetate Ointment 0.05% Halobetasol propionate Cream, ointment High Potency 0.1% Amcinonide Cream, ointment, lotion 0.05% Betamethasone dipropionate Cream, ointment 0.05% Desoximetasone Gel 0.25% Desoximetasone Cream, ointment 0.05% Fluocinonide Cream, ointment, gel 0.5% Triamcinolone acetonide Cream, spray Intermediate Potency 0.05% Clobetasone butyrate Cream 0.1% Clocortolone pivalate Cream 0.05% Desoximetasone Cream 0.1% Diflucortolone Cream, oily cream, ointment 0.02% Flumethasone pivalate Cream 0.025% Fluocinolone acetonide Cream, ointment 0.05% Flurandrenolide Cream, ointment, lotion, tape 0.005% Fluticasone propionate Ointment 0.1% Mometasone furoate 1 Cream, ointment, lotion 0.025% Triamcinolone acetonide Cream, ointment, lotion Low Potency 0.05% Desonide Cream, ointment 0.01% Fluocinolone acetonide Cream, solution 1% Hydrocortisone Cream, ointment, lotion, solution Objective 1  Glucocorticoids Routes of Administration –intra-articular Intra-articular (Depot glucocorticoids): Must be biologically active (joints lack 11β-HSD1 enzyme) Drugs: – Methylprednisolone acetate Indications: – rheumatoid arthritis, gout Objective 1  Glucocorticoids Local administration Benefits: Allow high local concentration Reduce systemic adverse effects Prevent HPA axis suppression & iatrogenic Cushing's syndrome Safer for long-term treatment (children) Objective 1  Glucocorticoids Pregnancy Prednisone – can be administered during pregnancy without fetal adverse effects Maternal liver (11β-HSD1) activates prednisone to prednisolone Placenta (11β-HSD2) converts prednisolone to prednisone Dexametasone Poor substrate for placental 11β-HSD2 Crosses the placenta in the active form  fetal circulation  fetal lung maturation (indicated in pregnant women at risk of preterm delivery) 11β-HSD, 11β-hydroxysteroid dehydrogenase Objective 1  The clinical use of prednisone is limited in that it cannot be used: A. in pregnant women B. as an oral drug C. in topical dermatologic preparations D. in long-term therapy  Case Study Eight-year-old Johnny finds that he can barely catch his breath at times, especially while exercising. His asthma comes and goes, but no therapy seems to stop the asthma attacks completely. Although his doctor is concerned that it could stunt Johnny’s growth, she eventually prescribes oral prednisone and tells Johnny’s parents to make sure he takes the medication every day. After a few weeks, Johnny’s asthma attacks subside, and he has a fairly normal childhood. The doctor pays close attention to Johnny’s linear growth. Two years later, Johnny’s doctor decides that a new inhaled glucocorticoid could be a safer medication for him. Johnny switches to the inhaled glucocorticoid and discontinues oral prednisone. Three days later, he develops a respiratory infection and is brought to the emergency department with low blood pressure and a temperature of 103°F. Based on his history of prednisone use, Johnny is immediately given hydrocortisone (cortisol) intravenously, as well as a saline infusion. Johnny recovers and for the next 6 months slowly tapers his oral prednisone dose with continued use of the inhaled glucocorticoid. Eventually, he is able to take the inhaled glucocorticoid alone as an effective therapy for his asthma. Golan et al. 2016. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4th ed  Case Study Why are cortisol analogues such as prednisone used for treating asthma? Why did abrupt cessation of oral prednisone precipitate Johnny’s clinical presentation in the emergency department? Why are inhaled glucocorticoids safer than oral glucocorticoids for long-term treatment of asthma? Why did the doctor monitor Johnny’s linear growth?  Case Study A 19-year-old man complains of anorexia, fatigue, dizziness, and weight loss of 8 months’ duration. The examining physician discovers postural hypotension and skin pigmentation and obtains routine blood tests. The physician finds hyponatremia, hyperkalemia, and acidosis and suspects Addison’s disease. A standard ACTH 1–24 stimulation test reveals an insufficient plasma cortisol response, which is compatible with primary adrenal insufficiency. The diagnosis of autoimmune Addison’s disease is made, and the patient must start replacement of the hormones he cannot produce himself. How should this patient be treated? Inhibitors of corticosteroids (cortisol) synthesis Drugs: Mitotane (Lysodren®) (antineoplastic) Aminoglutethimide Ketoconazole (antifungal drug) Metryrapone (Metopirone®) Osilodrostat (FDA-approved 2020) Levoketoconazole (FDA-approved 2021) Clinical use: Cushing’s syndrome, Cushing’s disease Adrenocortical carcinoma Objective 2  Inhibitors of corticosteroids synthesis INHIBITOR SITE OF ACTION Indications Adverse effects Mitotane Mitochondria Severe Cushing's disease Hypercholesterolemia Adrenocortical carcinoma Aminoglutethimide Side-chain cleavage Cushing’s syndrome Not recommended during enzyme (SCC) Breast cancer pregnancy Aromatase Ketoconazole High dose: SCC Fungal infections Gynecomastia (antifungal agent) Low dose: 17, 20 α- Cushing’s syndrome (off-label) hydroxylase Metyrapone 11β-hydroxylase Diagnostic HPA function Hypertension (antineoplastic agent) Cushing’s (off-label) Adrenocortical insufficiency Osilodrostat 11β-hydroxylase Cushing's disease Hypertension, edema Adrenocortical insufficiency Levoketoconazole 11β-hydroxylase Cushing’s syndrome Cardiac arrhythmias 17α-hydroxylase Alopecia Hypokalemia Objective 2  Glucocorticoid Receptor Antagonist Mifepristone (RU-486) (Korlym®, Mifeprex®) glucocorticoid and progesterone receptors antagonist Clinical use: termination of pregnancy (abortion - early in pregnancy) hyperglycemia secondary to Cushing's syndrome Objective 2 Synthesis inhibitors & Corticosteroids antagonists Mechanism of Action Aminogluthetimide Ketoconazole (low) Ketoconazole (high) - Levoketoconazole - 17α-Hydroxylase Cholesterol Pregnenolone 17-OH-Pregnenolone DHEA scc 3β-Dehydrogenase Progesterone 17-OH-Progesterone Androstenedione - 11-Deoxycorticosterone 11-Deoxycortisol Testosterone Metyrapone 11β-Hydroxylase Osilodrostat Corticosterone Cortisol Levoketoconazole Aldosterone - - Mifepristone Spironolactone (RU 486) Eplerenone Objective 2  A 55-year-old woman presents with signs of Cushing’s syndrome. Which of the following drugs would be expected to improve her condition? A. Dexamethasone B. Prednisone C. Cortisol D. Mitotane  Mineralocorticoids Aldosterone endogenous mineralocorticoid very low glucocorticoid effects Synthesized in the zona glomerulosa of the adrenal cortex – the synthesis is principally controlled by the renin-angiotensin system; less participation of ACTH – aldosterone does not produce feedback inhibition of ACTH 50-60% bound to circulating protein (albumin, transcortin) T1/2 = 20 minutes it is not available for therapeutic use Objective 3  Aldosterone Physiological effects Effects very potent salt-retaining activity – increases Na+ reabsorption from renal tubules (sweat & salivary glands) – increases excretion of K+ and H+ maintains salt and water balance and, thus, blood pressure Mechanism: increases expression of Na+/K+ ATPase & Na+ channels (ENaC) in the distal nephron Receptors Nuclear: mineralocorticoid receptor (MR)  increase gene transcription – MR expressed in the kidney; also in endothelial cells, vascular smooth muscle cells, cardiomyocytes, neurons (role in cardiovascular diseases -vascular injury, atherosclerosis) plasma membrane receptor(s)  nongenomic effects Objective 3  Aldosterone Site and mechanism of action Cortical collecting duct 1-5% of Na+ Blood Lumen (urine) reabsorption ↑ Na+ reabsorption ↓K+ reabsorption Spironolactone (MR antagonist): ↓ ENaC expression ↓ Na+/K+ ATPase expression Objective 3 Golan et al. 2012. Principles of Pharmacology.  Mineralocorticoid pathophysiology Hypoaldosteronism (aldosterone hypofunction) – Primary- decrease in aldosterone synthesis (most common) Congenital adrenal hyperplasia (genetic deficit of 21β-hydroxylase) – Addison’s disease (primary adrenal insufficiency) Cause: autoimmune; tuberculosis; metastatic cancer; hemorrhage Clinical: volume depletion, hyperkalemia, acidosis – Secondary – decrease in angiotensin II Due to decrease in renin production (hyporeninemic hypoaldosteronism) – Clinical hypoaldosteronism Mutation ENaC/MR  resistance to aldosterone (normal/high levels in blood) Objective 3  Mineralocorticoid pathophysiology Hyperaldosteronism (aldosterone hyperfunction) – Primary – excess aldosterone production adrenal hyperplasia, aldosterone-producing adenoma volume expansion, hypertension, endothelial dysfunction, insulin resistance Objective 3  Mineralocorticoid Receptor Agonist Fludrocortisone synthetic steroid minimal first-pass hepatic metabolism the most widely used mineralocorticoid pharmacologic actions are similar to those of aldosterone Use: replacement therapy in: Addison’s disease – fludrocortisone + hydrocortisone Salt-losing adrenogenital syndrome (congenital adrenal hyperplasia) Objective 3  Mineralocorticoid Receptor Antagonists Mechanism & Clinical use Spironolactone (Aldactone®) Eplerenone (Inspra®) Mechanism: competitive MR antagonists Spironolactone – also binds androgen/progesterone receptor Use: Edema associated with heart failure, renal dysfunction, corticosteroid therapy – Drugs of choice for treatment of ascites/edema in hepatic failure – Preserve cardiac function during cardiac ischemia and retard the development of heart failure (post- myocardial infarction) – Reduce mortality in patients with heart failure Hyperaldosteronism (primary) Hypertension (essential - high aldosterone levels; obesity-associated) To counteract K+-wasting effects of diuretics (used in conjunction with thiazides/loop diuretics) Objective 3  Mineralocorticoid Receptor Antagonists Adverse Effects Endocrine-related (Spironolactone) – due to interaction with other steroid (androgen/progesterone) receptors at extra-renal sites – impotence, gynecomastia (men) – menstrual irregularities, hair growth (women) – eplerenone - less hormonal side effects (more selective for MR) Hyperkalemia (both) Objective 3  Adrenal Androgens Dehydroepiandrosterone (DHEA) weak androgenic compound precursor of androgens and estrogens the major endogenous precursor of estrogens in women after menopause or with deficiency in ovarian function Pathophysiology Increased adrenocortical androgen production Congenital adrenal hyperplasia (deficiency steroid 21-β hydroxylase) Increased DHEA, testosterone; low cortisol, aldosterone Treatment: glucocorticoid + mineralocorticoid Objective 4 Deficiency of 21β-Hydroxylase  congenital adrenal hyperplasia  A newborn girl exhibited ambiguous genitalia, hyponatremia, hyperkalemia, and hypotension as a result of genetic deficiency of 21β-hydroxylase activity. Treatment consisted of fluid and salt replacement and hydrocortisone administration. In this type of adrenal hyperplasia in which there is excess production of cortisol precursors, which of the following describes the primary therapeutic effect of glucocorticoid administration? A. Increased adrenal estrogen synthesis B. Inhibition of adrenal aldosterone synthesis C. Recovery of normal immune function D. Suppression of ACTH secretion  Which of the following is a glucocorticoid and progesterone receptor antagonist? A. Aminoglutethimide B. Ketoconazole C. Mifepristone D. Spironolactone