1. Pituitary and adrenal hormones and the drugs that act on them (Glucocorticoids)

2. The pituitary and adrenal glands are major sites for the synthesis and release of hormones that profoundly affect the biochemistry and physiology of almost all cells, and which are crucial to the understanding of the actions of many endocrine, anti-inflammatory and other drugs

4. The anterior pituitary gland
The anterior pituitary gland secretes hormones that regulate:
the release of glucocorticoids from adrenal cortex ACTH
the release of thyroid hormones TSH
ovulation in the female and spermatogenesis in the male, and the release of sex hormones LH&FSH
growthGH
mammary gland structure and function PRL

5. Each anterior pituitary hormone is regulated by a specific hypothalamic releasing factor. Feedback mechanisms govern the release of these factors. Substances available for clinical use include:
growth hormone-releasing factor (sermorelin) and analogues of growth hormone (somatrem , somatropin)
thyrotrophin-releasing factor (protirelin ) and thyroid-stimulating hormone (thyrotrophin; used to test thyroid function)
octreotide and lanreotide, analogues of somatostatin, which inhibit growth hormone release
corticotrophin-releasing factor, used in diagnosis
gonadotrophin-releasing factor.

7. Posterior pituitary The posterior pituitary secretes: oxytocin
antidiuretic hormone (vasopressin ), which acts on V2 receptors in the distal kidney tubule to increase water reabsorption and, in higher concentrations, on V1 receptors to cause vasoconstriction. It also stimulates adrenocorticotrophic hormone secretion.
Substances available for clinical use are vasopressin and the analogues desmopressin and terlipressin.

8. Clinical use of antidiuretic hormone (vasopressin ) and analogues.
Diabetes insipidus: lypressin, desmopressin.
Initial treatment of bleeding oesophageal varices: vasopressin , terlipressin, lypressin. (Octreotide-a somatostatin analogue-is also used, but direct injection of sclerosant via an endoscope is the main treatment.)
Prophylaxis against bleeding in haemophilia (e.g. before tooth extraction): vasopressin , desmopressin (by increasing the concentration of factor VIII).
Felypressin is used as a vasoconstrictor with local anaesthetics.
Desmopressin is used for persistent nocturnal enuresis in older children and adults.

9. Adrenal Anatomy
small, triangular glands loosely attached to the kidneys
divided into two morphologically and distinct regions
adrenal cortex (outer)
adrenal medulla (inner)

12. Adrenocorticotrophic hormone (corticotrophin) & adrenal steroids
Adrenocorticotrophic hormone (ACTH) stimulates synthesis and release of glucocorticoids (e.g. hydrocortisone ), and also some androgens, from the adrenal cortex.
Corticotrophin-releasing factor from the hypothalamus regulates ACTH release, and is regulated in turn by neural factors and negative feedback effects of plasma glucocorticoids.
Mineralocorticoid (e.g. aldosterone) release from the adrenal cortex is controlled by the renin-angiotensin system.

13. Adrenal Cortex
Hormones produced by the adrenal cortex are referred to as corticosteroids.
These comprise mineralocorticoids, glucocorticoids and sex steriods.
The cortex is divided into three regions:
zona glomerulosa
zona fasciculata
zona reticularis

15. Regulation of Cortisol Release cont
Enhanced release can be caused by:
physical trauma
infection
extreme heat and cold
exercise to the point of exhaustion
extreme mental anxiety

16. Glucocorticoids
Common drugs used include hydrocortisone , prednisolone and dexamethasone .
Metabolic actions
Carbohydrates: decreased uptake and utilization of glucose accompanied by increased gluconeogenesis; this causes a tendency to hyperglycaemia.
Proteins: increased catabolism, reduced anabolism.
Lipids: a permissive effect on lipolytic hormones and a redistribution of fat, as observed in Cushing's syndrome.
NoneRegulatory actions
Hypothalamus and anterior pituitary gland: a negative feedback action resulting in reduced release of endogenous glucocorticoids.
Cardiovascular system: reduced vasodilatation, decreased fluid exudation.
Musculoskeletal: decreasing osteoblast and increasing osteoclast activity.

17. Inflammation and immunity:
acute inflammation: decreased influx and activity of leucocytes
chronic inflammation: decreased activity of mononuclear cells, decreased angiogenesis, less fibrosis
lymphoid tissues: decreased clonal expansion of T and B cells, and decreased action of cytokine-secreting T cells.
Mediators:
decreased production and action of cytokines, including interleukins, tumour necrosis factor-α and granulocyte macrophage colony-stimulating factor
reduced generation of eicosanoids
decreased generation of IgG
decrease in complement components in the blood
increased release of anti-inflammatory factors such as interleukin-10 and annexin 1.
Overall effects: reduction in the activity of the innate and acquired immune systems, but also decreased healing and diminution in the protective aspects of the inflammatory response.

18. The principal adrenal steroids are those with mineralocorticoid and glucocorticoid activity, but some sex steroids-mainly androgens-are also secreted. The mineralocorticoids affect water and electrolyte balance and the main endogenous hormone is aldosterone. The glucocorticoids affect carbohydrate and protein metabolism and the main endogenous hormones are hydrocortisone and corticosterone. The two actions are not completely separated in naturally occurring steroids, some glucocorticoids having quite substantial effects on water and electrolyte balance

19. .* In addition to their metabolic effects, glucocorticoids also have anti-inflammatory and immuno-suppressive activity, and it is for these actions that they are most commonly used therapeutically. When they are used as anti-inflammatory and immunosuppressive agents, all of their other actions are unwanted side-effects

20. Natural and Synthetic Adrenocorticosteroids
Antiinflamm Salt retaining
Glucocorticoids
Short acting
hydrocortisone, cortisone
prednisone, prednisolone,
methylprednisolone
Intermediate acting
triamcinolone ++
fluprednisolone
Long acting
dexamethasone
Mineralocorticoids
deoxycorticosterone

21. Synthetic steroids have been developed in which it has been possible to separate the glucocorticoid from the mineralocorticoid actions (see Table 27.2), but it has not been possible to separate the anti-inflammatory actions from the other actions of the glucocorticoids.

22. Hormones of the Adrenal Cortex
all adrenal cortex hormones are steroid
not stored, synthesized as needed O
C = O HO OH
CH2OH O HO
testosterone
cortisol

25. Mechanism of action of the glucocorticoids
Glucocorticoids interact with intracellular receptors; the resulting steroid-receptor complexes dimerise (form pairs) then interact with DNA to modify gene transcription: inducing synthesis of some proteins and inhibiting synthesis of others.
For metabolic actions, most mediator proteins are enzymes, e.g. cAMP-dependent kinase, but not all actions on genes are known.

26. For anti-inflammatory and immunosuppressive actions, some actions at the level of the genes are known:
inhibition of transcription of the genes for cyclooxygenase-2, cytokines (e.g. the interleukins), cell adhesion molecules and the inducible form of nitric oxide synthase
block of vitamin D3-mediated induction of the osteocalcin gene in osteoblasts and modification of transcription of the collagenase genes
increased synthesis of annexin-1, which is important in negative feedback on the hypothalamus and anterior pituitary and may have anti-inflammatory actions.
Some non-genomic (rapid) effects of glucocorticoids have also been observed.

27. Glucocorticoids
Drugs used: hydrocortisone , prednisolone and dexamethasone .
Metabolic actions
On carbohydrates: decreased uptake and utilisation of glucose and increased gluconeogenesis; this causes a tendency to hyperglycaemia.
On proteins: increased catabolism, reduced anabolism.
On fat: a permissive effect on lipolytic hormones, and a redistribution of fat, as in Cushing's syndrome.

28. Cushing’s Syndrome

30. Regulatory actions
On hypothalamus and anterior pituitary: a negative feedback action resulting in reduced release of endogenous glucocorticoids.
On vascular events: reduced vasodilatation, decreased fluid exudation.
On cellular events:
in areas of acute inflammation: decreased influx and activity of leucocytes
in areas of chronic inflammation: decreased activity of mononuclear cells, decreased proliferation of blood vessels, less fibrosis
in lymphoid areas: decreased clonal expansion of T and B cells and decreased action of cytokine-secreting T cells.

31. On inflammatory and immune mediators:
decreased production and action of cytokines including many interleukins, tumour necrosis factor-γ, granulocyte-macrophage colony-stimulating factor
reduced generation of eicosanoids
decreased generation of IgG
decrease in complement components in the blood.
Overall effects: reduction in chronic inflammation and autoimmune reactions but also decreased healing and diminution in the protective aspects of the inflammatory response.

32. Untoward Effects of Glucocorticoids
Due to:
Prolonged use: fever, myalgia, malaise, fluid and electrolyte imbalance, hypertension, hyperglycemia, myopathy, increased infections, ulcers, behavioral changes; pituitary-adrenal suppression
Abrupt withdrawal after prolonged use: acute adrenal insufficiency

33. unwanted actions of the glucocorticoids
Administration can be oral, topical and parenteral. The drugs are bound to corticosteroid-binding globulin in the blood and enter cells by diffusion. They are metabolised in the liver.
Unwanted effects are seen mainly with prolonged systemic use as anti-inflammatory or immunosuppressive agents (in which case all the metabolic actions are unwanted), but not usually with replacement therapy. The most important are:
suppression of response to infection
suppression of endogenous glucocorticoid synthesis
metabolic actions (see above)
osteoporosis
iatrogenic Cushing's syndrome

34. Untoward Effects of Glucocorticoids
Cardiovascular System
Prolonged Use: hypertension due to increased Na+ uptake
Rapid withdrawal: toxicity secondary to decreased Na+ uptake (hypocortism)
Direct effects due to steroid receptors on heart and smooth muscle; increased cardiac output and vascular tone
Skeletal Muscle
Impaired functioning
Muscle weakness and wasting

35. Untoward Effects of Glucocorticoids
Central Nervous System
Increased mood; euphoria
Behavioral changes; psychosis
EEG abnormalities
Increased excitability of nervous tissue
Gastrointestinal System
Increased gastric acid secretion
Increased fat absorption
Endocrine System
ACTH↓, ↓ TSH , ↓ FSH

36. Clinical Therapeutics1
GC are widely used for the suppression of inflammation in chronic inflammatory diseases such as asthma, RA, inflammatory bowel disease and autoimmune diseases, all with increased expression of inflammatory genes. 1

37. Clinical Therapeutics
Adrenal Cortical Insufficiency
Acute: life threatening; associated with abrupt withdrawal after prolonged therapy; GI abnormalities; dehydration, decreased Na+, increased K+ leads to CV weakness, lethargy, hypotension
Treatment: water, salt, cortisol, glucose
Chronic: (Addison’s disease): weakness, fatigue, decreased blood glucose, minor infections can lead to septic shock
Treatment: cortisol

38. Therapeutics Adrenal Hyperplasia Congenital adrenal hyperplasia
defect in cortisol synthesis; compensatory increase in ACTH
Cushing’s syndrome
secondary to pituitary adenoma
increased ACTH, glucocorticoids
round face, obesity, muscle wasting, poor wound healing, osteoporosis
treated surgically to remove tumor

39. Mineralocorticoids Regulate electrolyte and water balance
Aldosterone: most important mineralocorticoids in humans
Increase reabsorption Na+ from distal tubes and collecting ducts of kidney into plasma
Increase excretion K+ and H ↑ fluid volume
Increased aldosterone → hypokalemia, alkalosis
Decreased aldosterone → hyponatreuria, hyperkalemia

40. Mineralocorticoids
Fludrocortisone is given orally to produce a mineralocorticoid effect. This agent:
increases Na+ reabsorption in distal tubules and increases K+ and H+ efflux into the tubules
acts, like most steroids, on intracellular receptors that modulate DNA transcription causing synthesis of protein mediators
is used with a glucocorticoid in replacement therapy.

41. Mineralocorticoid antagonists
Antagonists of Adrenocorticoids
Mineralocorticoid antagonists
Spironolactone (diuretic): inhibits the actions of mineralocorticoids; competitive inhibitor; androgen antagonist
Use: treatment of primary aldosteronism