Adrenal pharm Flashcards
Overview of cortisol
Following a stressful event or an injury, the adrenal glands boost the production of cortisol.
Adrenal medulla is important, for maintaining sympathetic tone by means of secretion of the catecholamine epinephrine.
Adrenal cortex synthesizes and secretes steroid hormones essential for salt balance, intermediary metabolism, and androgenic actions.
Cortisol is part of the body’s fight-or-flight response.
- increases the amount of blood sugar available for fuel
- temporarily slows down some essential bodily functions
- helps boost the heart rate so a person can fight off or run away from a threat.
Cortisol also assists the body in routing a viral infection or healing damaged tissue.
Control pathway for cortisol
Systemic regulation of circulating cortisol levels by the hypothalamic pituitary adrenal (HPA) axis.
- Signaling to the hypothalamus by the normal circadian rhythm, stress, and pro-inflammatory cytokines increase release of corticotropin releasing hormone (CRH) from the hypothalamus.
- This acts on the pituitary to increase release of adrenocorticotropic hormone (ACTH) that acts to increase cortisol synthesis and secretion from the adrenal gland.
- Cortisol suppresses both CRF and ACTH at the pituitary and hypothalamus and a negative feedback loop.
Corticosteroid biosynthetic pathway
Corticosteroids are synthesized from cholesterol within the adrenal cortex
- 2 major groups = glucocorticoids + mineralocorticoids
- aldo and corticosterone share the first part of their biosynthetic pathway
- the last part is either mediated by aldo synthase (for aldo) or by 11 beta hydroxylase (for corticosterone)
Peripheral cortisol metabolism
The majority of circulating cortisol is bound to plasma proteins, the most important of which are corticosteroid-binding globulin (CBG);
- Only free-fraction is biologically active
The liver and kidneys are the primary sites of peripheral cortisol metabolism.
- cortisol = active form
- cortisone = inactive form
- 11-beta-hydroxysteroid dehydrogenase type 1 isoenzyme –> converts cortisone to cortisol
- –> expressed in many glucocorticoid target tissues.
- 11 B-HSD type 2 isoenzyme –> converts cortisol to cortisone
- –> found mainly in mineralocorticoid target tissues (kidney, colon, salivary glands) and in the placenta, in which it protects the cell from cortisol activation of the corticosteroid type 1 (mineralocorticoid) receptor.
Regulation of glucocorticoid (GC) levels in blood and tissues
- Circulating GC levels are tightly regulated by negative feedback inhibition at the hypothalamic-pituitary-adrenal (HPA) axis.
- Active GCs (cortisol in humans) circulate mostly bound to CBG (corticosteroid binding globulin) –> only ~4% are free to enter tissues.
- The inactive GCs (cortisone, 11-dehydrocorticosterone), the products of 11β-HSD2 metabolism mainly in kidney, circulates unbound to plasma proteins so all are available to enter tissues.
- Once inside the cell, there is another level of control by the presence of 11β-HSD1 (found in specific cells in the adult brain such as in hippocampus and cortex and other tissues such as liver and adipose).
- 11β-HSD1 regenerates active GCs from their inactive forms thereby effectively amplifying intracellular GC levels before they bind to MR and/or GR (depending on brain region).
- The activated receptors then translocate into the nucleus to activate the transcription of target genes.
Immunosuppressive effects of cortisol
- inhibits mediators of inflammation –> eicosanoids, serotonin, PAF, bradykinin
- inhibits inflammatory cytokines
Corticosteroid agonists and antagonists
Agonists
- glucocorticoids = prednisone
- mineralocorticoids = fludrocortisone
Antagonists
- synthesis inhibitors = ketoconazole
- receptor antagonists
- –> glucocorticoid antagonist = mifepristone
- –> mineralocorticoid antagonist = spirinolactone
Therapeutic applications for glucocorticoids
Addison’s disease Allergic diseases Adrenal diseases Arthritic diseases Rheumatoid arthritis Congenital adrenal hyperplasias (CAH) Eye diseases GI diseases Hypercalcemia Neurological diseases Pulmonary diseases Bronchial asthma Renal diseases Skin diseases Transplantation: to prevent rejection
Commonly used corticosteroids
- cortisol (hydrocortisone) - half life = 8-12 hours
- predisolone - half life = 12-36 hours
- prednisone - half life = 12-36 hours
- 9-a-fluorocortisol - half life = 12-36 hours
- betamethasone - half life = 36-54
- dexamethasone - half life = 36-54 hours
Esters used to alter duration of action
- succinate –> min-hours
- acetate –> days-weeks
- hexacetonide –> weeks
Routes of administration
Depot –> intramuscular preparations of glucocorticoid analogues last for days to weeks and can be an alternative to daily or alternate day oral glucocorticoids in the treatment of inflammatory diseases
Intra-articular administration –> indicated for inflammatory processes restricted to the joints, such as RA or gout
- useful in acute attacks of gout that are unresoponsive to colchicine or indomethacin
- biologically active preparation
Inhaled –> chronic asthma
- reduce symptoms by inhibiting airway inflammatory responses
Cutaneous –> topical glucocorticoids are available for a number of dermatologic disorders
- lichen planus
- psoriasis
- atopic dermatitis
- –> used at extremely low doses systemically
Oral hydrocortisome –> replacement therapy for primary adrenal insufficiency
- therapy must continue for life –> goal is to administer the smallest possible effective dose of glucocorticoid so as to minimize the adverse effects of chronic glucocorticoid excess
Therapeutic applications of glucocorticoids
Natural and synthetic glucocorticoids are used in both endocrine and non-endocrine disorders
Replacement therapy
- adrenal insufficiency
- given in physiological doses to establish the diagnosis and cause of cushing’s syndrome
- treatment of CAH –> challenge is balancing therapy to provide optimal control of androgens whilst avoiding over replacement with glucocorticoids –> excess glucocorticoid and excess androgens both have consequences
- –> glucocorticoid replacement therapy not only alleviates cortisol deficiency, but more importantly provides neg feedback to suppress ACTH secretion and prevent continued adrenal stimulation –> as a result, excessive 17 hydroxyprogesterone is not available as a substrate for excessive androgen production
Suppress inflammation and immune responses
- pharmacologic doses of glucocorticoids are used to treat patients with inflammatory, allergic and immunologic disorders
- if chronic, this supra-physiologic therapy has many adverse effects –> ranges from suppression of the hypothalamic pituitary adrenal axis and cushing’s syndrome to infections and changes in mental status
Pharmacological effects of glucocorticoids
Suppression of acth —> decreases endogenous glucocorticoid production
Metabolic effects
- increase glucose formation
- increase glycogen storage
- increase protein catabolism
- altered fat distribution
Involution of lymphoid tissue Inotropic effects on the heart CNS effects --> sense of euphoria Anti-inflammatory Immunosuppressive
Toxic effects of glucocorticoids seen with long term use
- hyperglycemia/glucosuria
- protein wasting –> myopathy, tissue thinning, osteoporosis, reduced wound healing
- peptic ulcers
- susceptibility to infection
- worsens glaucoma
- fetal abnormality
- herpes simplex of the cornea - contraindication
conditions reducing steroid metabolism
- liver disease
- terminally ill
- hypothyroidism
Secondary adrenal insufficiency due to exogenous steroids
- can be caused by prolonged administration of exogenous glucocorticoids
- adrenal cortex will atrophy
- results in decreased synthesis of all classes of adrenocortical hormones –> can be life threatening
- if a patient treated chronically with systemic glucocorticoids is switched to inhaled glucocorticoids, care must be taken not to stop the systemic dosing abruptly
- rapid withdrawal should be avoided –> dose should be reduced gradually, once a physiologic dose is reached, 20 mg hydrocortisone should be given daily for several months
- prominent features –> lethargy, anorexia, nausea, weight loss, headaches, fever
Considerations for duration of action
- fraction of the drug bound to plasma proteins
- affinity of the drug for 11-B-HSD II
- lipophilicity of the drug
- affinity of the drug for the glucocorticoid receptor
- –> clinically, it is most important to be aware of the potency of each agent relative to cortisol, especially when considering a change from one analogue to another that has different relative glucocorticoid and mineralocorticoid activities
