Adrenal corticosteroids, antagonists, corticotropin

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Chapter 35 Adrenal corticosteroids, antagonists, corticotropin

Diana C. Brown

Synopsis

In 1855, Dr Thomas Addison, assisted in his observations by three colleagues, published his famous monograph ‘On the constitutional effects of disease on the suprarenal capsules’ (Addison’s disease). It was not until the late 1920s that the vital importance of the adrenal cortex was appreciated and the distinction made between the hormones secreted by the cortex and medulla.

By 1936, numerous steroids were being crystallised from cortical extracts, but the quantities were insufficient to provide supplies for clinical trial.

In 1948, cortisone was made from bile acids in quantity sufficient for clinical trial, and the dramatic demonstration of its power to induce remission of rheumatoid arthritis was published the following year. In 1950, it was realised that cortisone was biologically inert and that the active natural hormone is cortisol. The pharmaceutical term for cortisol is hydrocortisone. The two terms are often used interchangeably. In this chapter, cortisol is used when describing endogenous hormone secretion, and hydrocortisone when describing exogenous drug administration. Since then many steroids have been synthesised, covering the wide range of efficacy and potency required by the many indications for systemic and local use. Steroids derive from natural substances, chiefly plant sterols. The ideal steroid drug, providing all the desirable and none of the undesirable effects of cortisol, remains elusive. Research showing the multiple molecular actions of steroids within the target cell has explained the difficulty of achieving the ideal, but may help to bring this closer.

About the same time as cortisone was introduced, adrenocorticotrophin (ACTH) became available for clinical use. Its use is now largely for diagnostic tests of the pituitary–adrenal axis.

Adrenal steroids and their synthetic analogues

The adrenal is a composite endocrine gland, and each zone of the cortex synthesises a different predominant steroid; a mnemonic is offered in Figure 35.1, in which the first letter of each word is the first letter of each zone and its corresponding steroid product. The principal synthetic pathways are illustrated in Figure 35.2.

Fig. 35.1 The zones of the adrenal gland and the hormones they secrete.

Fig. 35.2 Adrenal corticosteroid biosynthesis.

The principal hormone is the glucocorticoid cortisol secreted from the largest zone, the fasciculata; the mineralocorticoid aldosterone is secreted by the glomerulosa, and a number of androgens and oestrogens are secreted by the zona reticularis. The hypothalamic–pituitary system, through corticotropin releasing factor (CRF) and ACTH, controls cortisol and, to a lesser extent, aldosterone secretion; synthesis and secretion of aldosterone is regulated mainly by the renin–angiotensin system, and by variation in plasma K⁺ levels.

Adrenal corticosteroids are available for physiological replacement therapy, in primary (Addison’s disease), secondary adrenal insufficiency and congenital adrenal hyperplasia, but their chief use in medicine is for their anti-inflammatory and immunosuppressive effects (pharmacotherapy). Supraphysiological doses are generally required to achieve these pharmacological effects. Chronic use of supraphysiological doses has many adverse effects. Much successful effort has gone into separating glucocorticoid from mineralocorticoid effects.

In the account that follows, the effects of hydrocortisone will be described and then other steroids in so far as they differ. In the context of this chapter, ‘adrenal steroid’ means a substance with hydrocortisone-like activity. Androgens are described in Chapter 38.

Mechanism of action

Glucocorticoids stimulate the cell through both a classical cytosolic receptor that, on binding with agonist, translocates to the nucleus, and an unidentified membrane-bound receptor (Fig. 35.3). The classical receptor is responsible for so-called genomic effects through either activation or repression of DNA transcription. Up-regulation of gene transcription occurs when the receptor dimerises on specific DNA glucocorticoid response elements (GREs) with consequent recruitment of coactivator proteins. Many of the undesired effects of glucocorticoid occur through this pathway.

Fig. 35.3 Three general mechanisms of action of glucocorticoids and the glucocorticoid receptor in the inhibition of inflammation: non-genomic activation, DNA-dependent regulation, and protein interference mechanisms (e.g. NF-κBΒ elements). Red arrows denote activation, the red line inhibition, the blue arrow repression, and the red X lack of product (i.e. no mRNA). HSP, heat-shock protein; mRNA, messenger RNA; NF, nuclear factor; P, phosphate; TNF, tumour necrosis factor.

(Adapted from Rhen T, Cidlowski J A 2005 Antiinflammatory action of glucocorticoids – new mechanisms for old drugs. New England Journal of Medicine 353(16):1711–1723.)

Repression of DNA transcription occurs at slightly lower cortisol concentrations than required for transactivation. Through protein–protein interaction, the glucocorticoid–receptor complex inactivates pro-inflammatory transcription factors such as nuclear factor (NF)-κB and activator protein 1 (AP-1), preventing their stimulation of inflammatory mediators: prostaglandins, leukotrienes, cytokines and platelet-activating factor. These mediators would normally contribute to increased vascular permeability and subsequent changes including oedema, leucocyte migration and fibrin deposition.¹

There is a distinction between replacement therapy (physiological effects) and the higher doses of pharmacotherapy. However, the distinction is not absolute because cortisol is a stress hormone, and some of its physiological actions are triggered by the increased secretion of cortisol during acute or chronic stress. In the list that follows, the main physiological effects are those concerned with elimination of a water load, and mobilisation of glucose. The suppression of inflammatory mediators may also be seen as part of physiological homeostasis.

On inorganic metabolism

Cortisol is required for excretion of a water load. This action is due to maintenance of glomerular filtration, activation of atrial natriuretic factor, and inhibition of vasopressin secretion. These physiological effects are unrelated to the mineralocorticoid (Na⁺-retaining) action of cortisol that occurs at supraphysiological concentrations.

On organic metabolism

• Carbohydrate metabolism. Glycogenolysis and gluconeogenesis are increased and peripheral glucose utilisation is decreased (due to insulin antagonism).

• Protein metabolism. Anabolism (conversion of amino acids to protein) decreases but catabolism continues, so that there is a negative nitrogen balance with muscle wasting. The skin atrophies and this, with increased capillary fragility, causes bruising and striae. Healing of peptic ulcers or of wounds is delayed, as is fibrosis.

• Bone metabolism. Cortisol inhibits the number and function of osteoblasts, and the synthesis of collagen. Osteoporosis (reduction of bone protein matrix) is the main consequence of chronic glucocorticoid administration. Growth slows in children.

• Fat metabolism. Lipolysis is increased, and the secretion of leptin (the appetite suppressant) is inhibited. These actions lead to increased appetite and deposition of adipose tissue, particularly on shoulders, face and abdomen.

• Inflammatory response is depressed. Neutrophil and macrophage function are depressed, including the release of chemical mediators and the effects of these on capillaries.

• Allergic responses are suppressed. The antigen–antibody interaction is unaffected, but its injurious inflammatory consequences do not follow.

• Antibody production is lessened by heavy doses.

• Lymphoid tissue is reduced (including leukaemic lymphocytes).

• Renal excretion of urate is increased.

• Blood eosinophils reduce in number and neutrophils increase.

• Euphoria or psychotic states may occur, perhaps due to central nervous system (CNS) electrolyte changes.

• Anti-vitamin D action, see calciferol (p. 635).

• Reduction of hypercalcaemia, chiefly where this is due to excessive absorption of calcium from the gut (sarcoidosis, vitamin D intoxication).

• Urinary calcium excretion is increased and renal stones may form.

• Growth reduces where new cells are being added (growth in children), but not where they are replacing cells as in adult tissues.

• Suppression of hypothalamic–pituitary–adrenocortical feedback system (with delayed recovery) occurs with chronic use, so that abrupt withdrawal leaves the patient in a state of adrenocortical insufficiency.

The average daily secretion of cortisol is normally 10 mg (5.7 mg/m²). The exogenous daily dose that completely suppresses the cortex is hydrocortisone 40–80 mg, or prednisolone 10–20 mg, or its equivalent of other agents. Recovery of function is quick after a few days’ use, but when used over months, recovery takes months. A steroid-suppressed adrenal gland continues to secrete aldosterone.

Individual adrenal steroids

The relative potencies ¹ for glucocorticoid and mineralocorticoid (sodium-retaining) effects (Table 35.1) are central to the choice of agent in relation to clinical indication.

Table 35.1 Relative potencies of adrenal steroids

All drugs in Table 35.1 except aldosterone are active when swallowed, being protected from hepatic first-pass metabolism by high binding to plasma proteins. Some details of preparations and equivalent doses appear in the table. Injectable and topical forms are available (creams, suppositories, eye drops).

The selectivity of hydrocortisone for the glucocorticoid receptor is due not to a different binding affinity of hydrocortisone to the two receptors but to the protection of the mineralocorticoid receptor by locally high concentrations of the enzyme 11 β-hydroxysteroid dehydrogenase, which converts cortisol to the inactive cortisone. This enzyme saturates at concentrations of cortisol (and some synthetic glucocorticoids) just above the physiological range, which explains the onset of mineralocorticoid action with pathological secretion of cortisol, and pharmacological use of glucocorticoids.

Hydrocortisone

(cortisol) is the principal naturally occurring steroid; it is taken orally; a soluble salt can be given intravenously for rapid effect in emergency whether due to deficiency, allergy or inflammatory disease. A suspension (Hydrocortisone Acetate Inj.) is available for intra-articular injection.

Parenteral preparation for systemic effect: the soluble Hydrocortisone Sodium Succinate Inj. gives quick (1–2 h) effect; for continuous effect, about 6-hourly administration is appropriate. Prednisolone Acetate Inj. i.m. is an alternative, once or twice a week.

Tablet strengths, see Table 35.1.

Prednisolone

is predominantly anti-inflammatory (glucorticoid), biologically active, and has little sodium-retaining activity; it is the standard choice for anti-inflammatory pharmacotherapy, orally or intramuscularly.

Methylprednisolone

Fluorinated corticosteroids (triamcinolone, fludrocortisone)

Triamcinolone

has virtually no sodium-retaining (mineralocorticoid) effect. Muscle wasting may occasionally be severe, and chronic administration is therefore contraindicated. Anorexia and mental depression can occur at high dose.

Fludrocortisone

is a synthetic mineralocorticoid, which stimulates sodium retention. It can replace aldosterone when the adrenal cortex is destroyed (Addison’s disease). Fludrocortisone is also the drug of choice in most patients with autonomic neuropathy, in whom volume expansion is easier to achieve than a sustained increase in vasoconstrictor tone. Much higher doses of fludrocortisone (0.5–1.0 mg) are required when the cause of hypotension is a salt-losing syndrome of renal origin, e.g. after an episode of interstitial nephritis.

Dexamethasone and betamethasone

Aldosterone

(t_½ 20 min), is the principal natural salt-retaining hormone. After oral administration, it is rapidly inactivated in the first pass through the liver and is not available for therapeutic use.

Spironolactone

(see p. 550) is a competitive mineralocorticoid (aldosterone) antagonist. It is used in the treatment of primary hyperaldosteronism, as a diuretic in resistant hypertension, and when severe oedema is due to secondary hyperaldosteronism, e.g. cirrhosis, congestive cardiac failure. Long-term treatment increases survival in cardiac failure, possibly through blocking the fibrotic effect of aldosterone upon the heart. The dose of spironolactone is limited by its anti-androgen activity. Eplerenone has greater selectivity than spironolactone for the mineralocorticoid than androgen receptor, but has lower efficacy in blocking aldosterone and may need to be used together with amiloride.

Beclometasone, budesonide, fluticasone, mometasone and ciclesonide

are potent soluble steroids suitable for use by inhalation for asthma (see p. 474) and intranasally for hay fever. Patients swallow about 90% of an inhalation dose, which is then largely inactivated by hepatic first-pass. The drugs are listed in order of development; some newer agents possess properties (first-pass metabolism, high protein binding and lipophilicity) that may increase pulmonary residence time and reduce systemic effects. The main protection against these effects is simply that absorption through mouth, lungs and gut is low relative to the amounts used in systemic administration. The risk of suppression of the hypothalamic–pituitary–adrenal (HPA) axis is infrequent and dose dependent. The greatest risk of suppression appears to occur with high-dose fluticasone usage in children, who may present with hypoglycaemia and acute adrenal insufficiency.