Corticosteroids Flashcards
What are corticosteroids?
They are any steroid hormones (excluding sex hormone) which are produced by the cortex of the adrenal gland or any synthetic equivalent
What are the zones of the adrenal cortex
Zona glomerulosa (outer)
Zona fasciculate (middle)
Zona reticularis (inner)
What hormones reproduced in the zona glomerulosa ?
mineralcorticoids such as aldosterone
What is the function of aldosterone?
Regulates water and electrolyte balance
What hormones are produced in the zona fasciculate?
Glucocorticoids
Cortisol and hydrocortisone
What are the functions of glucocorticoids?
carbohydrate, protein and lipid metabolism
Suppression of inflammation and immune response
Mediator of the stress response
What hormone is produced by the zona reticularis?
Androgens
Dehydroepiandrosterone
What is the function of dehydroepiandrosterone?
Stimulates and maintains mascularisation
What types of cells are found in the medulla of adrenal glands?
Chromaffin cells
What hormones are produced by chromaffin cells?
Catecholamines
E.g. adrenaline, noradrenaline
What is the function of cathecolamines?
Neurohormones; stimulates sympathetic CNS
Flight or fight respones
Cathecholamines have an _______ side chain
amine
What is the difference between mineral & glucocorticoids and catecolamines?
Mineralcorticoids and glucocorticoid are able to pass through the cell and bind to intracellular receptors whilst catecholamines behave like peptide hormones and are unable to do so
How are glucocorticoids regulated?
HPA axis
Hypothalamic- pituitary- adrenal axis
Response to stress involves the HPA axis. Give examples of “stress”
Acute illness
Injury
Pain
Anxiety
Infection
Blood loss
Surgery
Hypoglycaemia
Briefly outline the HPA axis
Hypothalamus released CRH (corticotrophic releasing hormone
CRH stimulates the anterior pituitary gland to release ACTH (adrenocorticotropic hormone)
ACTH stimulates the adrenal cortex to synthesise and secrete cortisol (zona fasciculate)
ACTH stimulation has a modest effect on __________.
Mineralcorticoid (aldosterone) release
Excess cortisol acts as a _____________ to inhibit ________ and ______ hormones.
Negative feedback loop
CRH and ACTH
___________ is produced by the posterior pituitary gland. What is its function in the stress response?
Vasopressin (Antidiuretic hormone)
It functions to stimulate the production of ACTH in the anterior pituitary gland
Circadian rhythm in glucocorticoid secretion is at its highest in the _________.
morning
Circadian rhythm in glucocorticoid secretion is at its lowest in the _________.
evening
HPA has a modest effect on the production of which corticosteroid hormone?
Aldosterone
HPA is also referred to as the …
stress response axis
What stimulates the release of aldosterone?
HPA axis (moderate release)
Angiotensin II
What system regulates the release of aldosterone?
Renin-angiotensin- aldosterone- system (RAAS)
Briefly describe how the RAAS system regulates aldosterone production
Renin is released from the kidney into the blood and converts angiotensinogen into angiotensin-I
Angiotensin converting enzyme (ACE) from the vascular endothelium cleaves angiotensin-I into angiotensin-II
Angiotensin II acts on adrenal cortex (Zona glomerulosa) to release aldosterone
In what way is angiotensin II able to increase blood pressure?
Angiotensin II binds to its receptor and has an effect on nitric oxide (vasodilator) synthesis; this increases vasoconstriction
Angiotensin II stimulated the release of ACTH from the adrenal cortex
Where are glucocorticoid receptors found?
They are found in most cell types
How is cortisol found in the blood?
Cortisol is found bound to corticosteroid binding globulin (CBG)
Some cortisol is also found bound to albumin
Whilst bound to CBG or albumin, steroids are biologically active. True or false
False
They are biologically inactive
Steroids enter cells as _________ molecules
free
Intracellular steroid receptors are bound to what proteins?
stabilising proteins e.g. Heat shock proteins (Hsp)
Others (X)?
What happens when steroids initially bind to their intracellular receptors ?
Stabilising proteins are released
The steroid-receptor complex enters the nucleus in the form of a ________.
dimer
What component on the gene do glucocorticoid-receptor complex bind to?
GRE
Glucocorticoid response elements
What is the function of GRE stimulation and inhibition?
regulate gene transcription (activation or inhibition) thus potentially yielding protein production
What the onset of steroid hormones? Why is this?
hours to days
due to longer duration of exprssion
Class I Nuclear receptors are characterised by the formation of _________.
homodimers
Class II nuclear receptors are characterised by the formation of _________ with __________ receptors
heterodimers
Retinoid X receptors (RXR)
Give examples of tissues which contain mineralcorticoid nuclear receptors
Kidney
Sweat ands salivary glands
Epithelia of colon and bladder
The MOA of mineralcorticoids is similar to that of glucocorticoids. In what way does it differ?
-the steroid receptor complex binds to the MRE (mineralcorticoid receptor complex)
-this increases the number of Na+/K+ pumps expressed on the distal tubule
What is the effect of increased expression of Na+/K+ pumps in the distal tubules?
Increased Na+ reabsorption into vasculature (increase in serum Na+)
This therefore leads to passive H2O reabsorption
This increases water retention in the serum
What is the physiological effect of aldosterone?
maintain adequate fluid volume and electrolyte balance for normal cardiac output and arterial BP
What is the MOA of aldosterone ?
Increase Na+/K+ pump expression in distal tubules
Increase Na+ reabsorption and passive reabsorption of water
Increase efflux of H+ and K+ ions, causing increased K+ excretion from kidneys
Mineralcorticoid sensitive organs produce which enzyme to prevent them from responding to cortisol? Briefly explain why this is necessary?
11beta hydroxysteroid dehydrogenase type 2 (11B HSD)
This is because cortisol and aldosterone are equiactive Mineralcorticoid receptors- cortisol can activate MRs; this can leads to some adverse effects
What is the function of 11beta hydroxysteroid dehydrogenase type 2 (11B HSD) ?
Convert cortisol to inactive cortisone
In liquorice toxicity ________ found in liquorice roots inhibits 11B HSD activity. What is the effect of this.
Glycyrrhizin
Cortisol build up in mineralcorticoid sensitive tissues such as the kidney
This can lead to:
-hypokalemia (low serum K+)
-hypernatremia (high serum Na+)
-water retention
What symptoms can be expected in >40 years olds with a history of heard disease/ HBD who experience liquorice toxicity?
Oedema
High blood pressure
Muscle cramping or weakness
Abnormal heart rhythm and heart failure
What are the inflammatory actions of glucocorticoids?
Inhibition of genes regulating expression of inducible COX-2 and NOS and most inflammatory cytokines (decreased production and action of interleukins, granulocyte macrophage CSF, TNFa, INFy)
Upregulation of the expression of annexin A1
Acute inflammation (influx and activity of leucocytes)
Chronic inflammation (decreased activity of mononuclear cells, decreased angiogenesis, decreased fibrosis)
What is the function of annexin A1?
directly inhibits PLA2 (phospholipase 2) and COX-2)
PLA2 metabolised the production of AA
this overall lead to decreased prostaglaindin and leukotriene synthesis
An inhibition of genes regulating expression of inducible COX2 and NOS leads to …
decreases prostanoids
decreased vasodilation
decreased vascular permeability
What immunosuppressive actions are caused by glucocorticoids?
decreased T lymphocyte activation and proliferation
decreased action of cytokine secreting T lypmphocytes
decreased production of plasma cells and antibodies
decreased phagocytosis of antigens by macrophages
Prostanoids are a __________ of eicosanoids
subclass
What are the adverse effects of glucocorticoids?
- increased infections due to depressed host immune system (oral candiasis whilst on inhaled corticosteroids)
-decrease protective aspects of inflammation- impaired wound healing, peptic ulcers (loss of protective prostanoid effect) - prostanoids protect the GI mucosa
What does adrenocorticoid insufficiency refer to ?
this is when adrenal glands produce insufficient corticosteroid hormones
What are the 3 types of adrenocorticoid insufficiency?
Primary
Secondary
Tertiary
What is the cause of primary adrenocorticoid insuffiency?
Impairment of adrenal glands
What percentage of cortisol is bound to CBG?
77%
80% of primary adrenocorticoid insufficiency is caused by …
Autoimmune disease Addisons disease
Addisons disease is also known as adrenal insufficiency where not enough cortisol and aldosterone are produced
Give examples of associated health condition which can develop as a result of addisons disease
diabetes
Underactive thyroid
List other causes of primary adrenocorticoid insufficiency
congenital adrenal hyperplasia
adenoma
What is hyperplasia
increase in the number of cells in an organ/ tissue
Secondary adrenocortical insufficiency is due to an impairment in _____________.
the pituitary gland
Give an example of a condition that can lead to secondary adrenocortical insufficiency
Pituitary adenoma
which supresses production of ACTH
Tertiary adrenocortical insufficiency is due to _________.
hypothalamic disease
Give examples of hypothalamic disease which lead to tertiary adrenocortical insufficiency
brain tumours
sudden withdrawal from long-term exogenous steroid use
lead to decrease in release of CRH
Left untreated, adrenocortical insufficiency can lead to …
Adrenal crisis (medical emergency)
symptoms appear quickly and severely
List some signs and symptoms of an adrenal crisis
-fever
-syncope
-convulsions (fast, rhythmic uncontrolled movements)
-hypoglycaemia
-hyponatremia (high Na+)
-severe vomiting and diarrhoea
What is the treatment for adrenocortical insufficiency?
Daily hydrocortisone (replace cortisol)
Daily fludrocortisone (replace aldosterone)
Glucocorticoids affect carbohydrate, protein and lipid metabolism. State specifically what these metabolic effects are.
Increased liver glucose synthesis from amino acids and fatty acids (gluconeogenesis). The enzymes involves in protein break down are upregulated to provide amino acids and lipolysis is activated.
Reduce glucose uptake and utilisation by peripheral tissues.
What is the effect of cortisol of plasma glucose? What is the mechanism for this
Increases plasma glucose levels
Reducing glucose uptake and utilisation by peripheral tissues by:
-antagonising the effect of insulin on peripheral tissues
-stimulating the translocation of glucose transporters from the plasma membrane into the cell
Cortisol reduces glucose uptake and utilisation in peripheral tissues. What is the purpose of this?
to increase the availability of blood glucose to the brain
What are the adverse metabolic effects of glucocorticoids?
-due to increased glucose synthesis- hyperglycaemia, worsening diabetes
-protein break down affects multiple tissues including skin and muscle; decreased muscle mass, thinning of the skin (fragile and easy to bruise)
-due to increase free fatty acids, there is a further insulin increase in insulin resistance and a dramatic redistribution of fat
What are the adverse metabolic effects of glucocorticoids?
-due to increased glucose synthesis- hyperglycaemia, worsening diabetes
-protein break down affects multiple tissues including skin and muscle; decreased muscle mass, thinning of the skin (fragile and easy to bruise)
-due to increase free fatty acids, there is a further insulin increase in insulin resistance and a dramatic redistribution of fat
The redistribution of body fat as a result of glucocorticoids presents as …
- buffalo hump (increased fat in the back of the neck)
- moon face (increased facial fat)
- loss of fat in body extremeties
Glucocorticoids have other adverse systemic effects outside of those associated with metabolism. Briefly state them
Diverse neurological effects and behavioural changes
Skeletal effect
What is the MOA of diverse neurological effects and behaviour changes that can stem from glucocorticoids?
MOA is unclear
Give examples of diverse neurological effects and behavioural changes associated with glucocorticoids
Insomnia and agitation
Psychological: mild (euphoria, anxiety); pronounced, (manic- depression)
What the MOA of skeletal changes associated with glucocorticoids?
Decreased Ca2+ absorption into GI tract
Increased Ca2+ excretion into the kidneys
Reduce osteoblast function (deposition of bone matrix affected)
Increased osteoclast activity
Skeletal changes observed as a result of glucocorticoid use can lead to the development of _________.
osteoporosis
What is the function of 11beta hydroxysteroid dehydrogenase (11B HSD)?
convert cortisol to cortisone (inactive)
In higher, non physiological concentrations, glucocorticoids have some mineralcorticoid actions. True or false
True
Cortisol and aldosterone are equiactive on mineralcorticoid receptors
What is the MOA of cortisol on mineralcorticoid receptors ?
-swamping protective action of 11BHSD and act on mineral corticoid receptors
-increases Na+ and water reabsorption in distal tubules
- increase K+ and H+ efflux from the tubules, this increases K+ excretion
What are the adverse effects of glucocorticoid action on mineralcorticoid receptors?
Hypertension
Oedema
What is Cushings syndrome?
a collection of symptoms caused by high levels of glucocorticoid signalling
caused by high levels of cortisol/glucocorticoid drugs in the body
List some symptoms of cushings syndrome
Euphoria (depression or psychotic symptoms and emotional lability)
Buffalo hump
Hypertension
Thinning skin
Thin arms and legs (muscle wasting)
Benign intracranial hypertension
Cataracts (increased glucose to brain??? cranial glucose availability?)
Moon face with red (plethoric) cheeks
increased abdominal fat
Avascular necrosis of femoral head
Easy bruising
poor wound healing
Also:
osteoporosis
tendency to hyperglycaemia
negative nitrogen balance
increased appetite
increased susceptibility to infection (immunosuppressive action; anti-inflammatory action)
obesity
Excessive exposure to glucocorticoids can lead to _____________.
cushings syndrome
Cushings syndrome can be caused by …
Disease: ACTH secreting pituitary gland tumour
Prolonged administration of large doses of glucocorticoid drugs (iatrogenic cushings syndrome)
What is the treatment for cushings syndrome?
Decrease or withdraw use of corticosteroids
Withdrawal of corticosteroids must be done _________. Why is this?
Gradually
to avoid any unwanted effects
avoid adrenal insufficiency
Chronic glucocorticoid therapy can be described as…
taking a dose of 30 mg of daily hydrocortisone or equivalent for greater than/equal to 4 weeks
Negative feedback effect on CRH and ACTH
Reduction in release of ACTH
Overtime this can result in the atrophy of cortisol producing cells in the adrenal gland (zona fasciculata)
What is the consequence of adrenal atrophy?
can reduce normal levels of ACTH stimulated cortisol release
this results in signs and symptoms of adrenal insufficiency
How can you avoid adrenal insufficiency following glucocorticoid withdrawal? Why is it important to do it this way?
gradual tapering of dosages over a period of weeks to months prior to complete discontinuation
This is recommended to allow time for recovery of the HPA axis
What is the treatment suggested for adrenal insufficiency?
Hydrocortisone (first line drug to replace cortisol); closest to cortisol
Absorbed quicker than other corticosteroids
adult daily dose of hydrocortisone is usually 15-30mg split into 2-3 doses
the highest dose is administered in the morning and the lowest in the evening to follow cortisol circardian rhythm
this enables a slow recovery to reach full adrenal function (8weeks to >18 months)
Adrenal insufficiency can rarely but quickly lead to __________ and _________.
Acute adrenal insufficiency
Adrenal crisis (medical emergency)
What are the physiological effects of an adrenal crisis?
coma or death if left untreated
reduce oxygen supply to brain and can lead to brain damage
What are some symptoms of an adrenal crisis?
Abdominal pain
pale, cold and clammy skin
confusion
rapid, shallow breathing
dizziness
severe dehydration
fever
severe drowsiness or unconsciousness
headache
severe muscle weakness
hypotension
severe, persistent vomiting and diarrhoea
What is the treatment of an adrenal crisis?
intravenous fluids
intravenous hydrocortisone
Give some examples of conditions treated with corticosteroids
Adrenal insufficiecy
cerebral oedema and increased intracranial pressure (brain tumour, meningitis, trauma, cerebrovascular events)- this is because of the anti-inflammatory action of corticosteroids.
Collagen vascular diseases e.g. lupus, polymyositis, temoporar arteritis, mixed connective tissue disease synfrime
Dermatologic conditions-psoriasis, dermatitis
GI diseases- UC, crohns disease, celiac disease (immunosuppressive effect)
Haematologic diseases- malignancies, hemolytic anaemia,
Hepatic diseases- autoimmune hepatitis
MS (immunosuppresive effect)
pulmonary diseases- asthma, chronic bronchitis, aspiration pneumonia
rheumatic diseases and joint ailments- rheumatic arthritis, rheumatic carditis, osteoarthritis
Refractory shock (septic, anaphylactic)
solid tumours (breast)
tissue grafts and organ transplants
All natural an synthetic glucocorticoids are well absorbed from the GI tract. True or false
true
In what manner do glucocorticoids exist in blood plasma?
Protein bound
77% protein bound?
To CBG (corticosteroid binding globulin) or albumin
How is hydrocortisone metabolised?
rapidly degraded in the liver by reduction
Conjugated with glucoronic acid and excreted in the urine
What is the plasma half life of hydrocortisone?
1.5 hours
The time course of the effect of hydrocortisone is not representative of plasma concentration. What doe this mean?
A longer duration of action ?
What is the biological latency of hydrocortisone?
2-8 hours
Many glucocorticoids in therapeutic use have different _________ and _________.
potency
physiochemical propertis
What are the different routes of administration of glucocorticoids?
Oral
Inhaled (aerosol)
Intramuscular
Intravenous
Intra-articular (entering joint)
Topically (ointment or spray)
What is the benefit of topical administration of glucocorticoids ?
Diminishes the likelihood of systemic toxic effects
When on prolonged treatment of glucocorticoids, what manner of administration may decrease the suppression of HPA and other unwanted effects?
administration on alternative days
What is the drug of choice for replacement therapy (cortisol)
hydrocortisone
Cortisone is a prodrug and therefore remains inactive until converted to __________.
hydrocortisone
Cortisone is uses primarily as an anti-inflammatory agent due to
the mineral corticoid effects
(increased BP, oedema)
Deflazacort is a prodrug. How is it activated?
converted by plasma esterases into active metabolite
Deflazacort has a similar utility to what other glucocorticoid compound?
Prednisolone
What compound is the drug of choice for anti-inflammatory and immunosuppresive effects?
Prednisolone
What compound is inactive until converted to prednisolone?
Prednisone
What is the use of methylprednisolone?
immunosuppresive and anti-inflammatory effects
What is the drug of choice for ACTH suppression ?
dexamethasone
Dexamethasone is used as a potent anti-inflammatory and immuno-suppressive agent when …
water retention is undesirable (for instance where there is cerebral oedema)
Affinity for mineralcorticoid receptors?
Minimal sodium retention
State the use of betamethasone
Anti-inflammatory and immunosuppresive agent especially where water retention is undesirable
What is the drug of choice for mineralcorticoid effects?
Fludrocortisone
Topical corticosteroids therapies are in the DPF. What can they be used for?
oral ulcerations
What is an oral ulcer?
small, painful patch/lump inside the mouth
Why are glucocorticoids indicated for treatment of oral ulcerations?
calm down immune system
help reduce pain and swelling
helping ulcers heal
Beclomethasone is delivered by …
pressurised inhalation (spray)
50ug of beclomethasone is used to treat/manage…
oral ulcerations
Betamethasone are available as _______. How are they administered and what are they used to treat?
soluble tablets (500ug)
they can be dissolved and used as a mouthwash used to treat oral ulcerations
Hydrocortisone is available in the DPF as…
1% cream
oromucosal tablets
How are hydrocortisone oromucosal tablets administered?
allowed to dissolve next to the oral ulcer
List some dental considerations for patients on long term glucocorticoid therapy
decreased resistance to infection
poor wound healing response
source of oral infection (carious teeth, inflammed tissue) should be promptly treated due to immunosuppression
suppressed pituitary adrenal function
schedule appointment in the morning when circulating cortisol concentrations are highest
check medical history and consult GP
a patient with adrenal insufficiency may become hypotensive under the stress of a dental visit
How should patients on long term glucocorticoid therapy be managed in the dental practice ?
lay patient flat
give oxygen
transfer patient urgently to hospital
BP must be monitored and presence of osteoporosis (jaw bone and loss of tooth support)
avoid analgesics such as NSAIDs; increases risk of GI bleed (loss of prostanoid protection)
How many interactions are listed in the BNF for hydrocortisone? Of these, how many are severe?
> 150
100
