Transcript 4 pit &adrenal326

Pituitary and adrenal hormones
and the drugs that act on them
(Glucocorticoids)
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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
The anterior pituitary gland
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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
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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 thyroidstimulating 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.
Posterior pituitary
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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.
Clinical use of antidiuretic hormone
(vasopressin ) and analogues.
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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.
Adrenal Anatomy
• small, triangular glands loosely attached
to the kidneys
• divided into two morphologically and
distinct regions
- adrenal cortex (outer)
- adrenal medulla (inner)
Adrenocorticotrophic hormone
(corticotrophin) & adrenal steroids
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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 reninangiotensin system.
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
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
Glucocorticoids
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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.
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Inflammation and immunity:
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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.
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Mediators:
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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.
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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
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.* 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
Natural and Synthetic
Adrenocorticosteroids
Antiinflamm
Salt retaining
Glucocorticoids
Short acting
hydrocortisone, cortisone
prednisone, prednisolone,
methylprednisolone
+
+
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Intermediate acting
triamcinolone
fluprednisolone
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Long acting
dexamethasone
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Mineralocorticoids
deoxycorticosterone
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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.
Hormones of the Adrenal Cortex
• all adrenal cortex hormones are steroid
CH2OH
HO
C=O
OH
HO
O
O
testosterone
cortisol
• not stored, synthesized as needed
Mechanism of action of the
glucocorticoids
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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.
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.
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Glucocorticoids
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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.
Cushing’s
Syndrome
Regulatory actions
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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.
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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.
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
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Abrupt withdrawal after prolonged use:
acute adrenal insufficiency
unwanted actions of the glucocorticoids
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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:
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suppression of response to infection
suppression of endogenous glucocorticoid synthesis
metabolic actions (see above)
osteoporosis
iatrogenic Cushing's syndrome
Untoward Effects of Glucocorticoids
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Cardiovascular System
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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
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Impaired functioning
Muscle weakness and wasting
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Central Nervous System
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Increased mood; euphoria
Behavioral changes; psychosis
EEG abnormalities
Increased excitability of nervous tissue
Gastrointestinal System
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Untoward Effects of Glucocorticoids
Increased gastric acid secretion
Increased fat absorption
Endocrine System
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ACTH↓, ↓ TSH , ↓ FSH
Clinical Therapeutics
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1
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GC are widely used for the suppression of
inflammation in chronic inflammatory diseases
such as asthma, RA, inflammatory bowel
1
disease and autoimmune diseases, all with
increased expression of inflammatory genes.
Clinical Therapeutics
Adrenal Cortical Insufficiency
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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
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Chronic:
(Addison’s disease): weakness, fatigue, decreased
blood glucose, minor infections can lead to septic shock
 Treatment: cortisol
Therapeutics
Adrenal Hyperplasia
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Congenital adrenal hyperplasia
defect in cortisol synthesis; compensatory
increase in ACTH
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Cushing’s syndrome
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secondary to pituitary adenoma
increased ACTH, glucocorticoids
round face, obesity, muscle wasting, poor wound
healing, osteoporosis
treated surgically to remove tumor
Mineralocorticoids
Regulate electrolyte and water balance
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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
Mineralocorticoids
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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.
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Antagonists of Adrenocorticoids
Mineralocorticoid antagonists
Spironolactone (diuretic): inhibits the actions of
mineralocorticoids; competitive inhibitor;
androgen antagonist
Use: treatment of primary aldosteronism