Corticosteroids and immune modulatory agents Flashcards
What happens in the brain when the body is under stress
- Hypothalamus releases corticotrophin releasing factor
- This stimulated the anterior pituitary gland to release adrenocorticotrophin hormone
- This stimulates the adrenal cortex to release mineralocorticoids and glucocorticoids
What is the release of mineralocorticoids and glucocorticoids controlled by
RAS
What is another name for glucocorticoids
corticosteroids
Name the 2 main types of endogenous steroids
- mineralocorticoids
- glucocorticoids
What do mineralocorticoids include
Aldosterone
What are mineralocorticoids involved in
Water and electrolyte balance
What do glucocorticoids include
Hydrocortisone
What are glucocorticoids involved in
Carbohydrate and protein metabolism
Why are glucocorticoids used for clinically
Used for their anti-inflammatory, immunosuppressive and steroid- replacement abilities
List soem synthetic corticosteroids
- Glucocorticoids,
- glucocorticosteroids,
- steroids
What are synthetic corticosteroids
They are analogues of endogenous adrenal steroid hormones
Describe the qualities of synthetic corticosteroids
- Anti-inflammatory
- Immunosuppressive
- Proliferate
- Vasoconstricting
Talk through the mode of action of synthetic corticosteroids
Bind to intracellular steroid receptors which then bind to specific DNA sequences to modify gene transcription
OR
They interact in various ways with cellular membranes and their receptors
What effect do corticosteroids have on the body
They stop transcribing genes and the subsequent pro inflammatory protein that drive so many choleric inflammatory disease
Which protein transport corticosteroids once they are absorbed
Transcortin and albumin
Which has better anti inflammatory and immunosuppressive qualities mineralocorticoids or corticosteroids
Corticosteroids
Name some clinically useful steroids
- Hydrocortisone
- Prednisolone
- Betamethasone
- Fludrocortisone
How can steroids be given
Most active orally but can be given through:
1. IV
2. Intra muscular
3. Eye drops
4. Ointment
5. Inhaled
Talk through the mode of action of glucocorticoids
Bind to intracellular receptors and results in reduced production of factors involved in immune and inflammatory responses
What do glucocorticoids do
They induce phospholipase release and suppress COX2
What does the inducing of phospholipase release and suppress COX2 lead to
- less IL-1,-2,-3,-6, TNF alpha and interferon gamma
- Less COX-2
- Endothelial leukocyte adhesion molecule 1
- Less release of histamine and leucotrienes from mast cells and basophils
- Less fibroblast production
- less induction, proliferation and effector phase of lymphocytes
List some diseases corticosteroids can be used as therapeutics for
- Asthma and other allergies
- Eczema/ dermatitis, lichen planus, vasculitis
- Erythema multiform
- Steven Johnsons syndrome
- Oral ulcerations
- Behçet’s disease
- Some blood disorders
- inflammatory bowel disease
- immunosuppression after organ failure
- Addisons disease
Where is cortisol secreted fro
The adrenal cortex
How much cortisol is secreted daily
The adrenal cortex secretes 20mg of cortisol daily
How much is 20mg of cortisol in prednisolone
5mg
What is an adrenal crisis
It is a medical emergency caused by lack of cortisol
When does an adrenal crisis occur
A sudden cessation of steroids therapies or not increasing dose sufficiently during period of physiological stress
What might patents suffering from an adrenal crisis experience
- Lightheadness
- Dizziness
- Weakness
- Sweating
- Abdominal pain
- Nausea
- Vomitting
How do we manage an adrenal crisis
Immediate replacement of IV or IM hydrocortisone and blood pressure support
What can an unmanaged adrenal crisis lead to
Death through overwhelming hypovolaemic or septic shock
What term is used to group the adverse effect of corticosteroids steroids
Cushings syndrome
What is cushings syndrome
Term given to commonly encountered adverse sequelae effects with long term or very high dose potent steroids
List some effects cushings syndrome has on the brain
- Euphoria
- Depression
- Psychosis
- Benign intracranial HTN
- Emotional liability
- Sleep disturbances
List some effects cushings syndrome has on the face
- Cataracts in eyes
- Moon face
List some effects cushings syndrome has on the neck and back
Fat deposition on back of base of neck
List some effects cushings syndrome has on the Blood pressure
Hypertension
List some effects cushings syndrome has on the abdomen
Increased fat deposition on the abdomen
List some effects cushings syndrome has on muscles
Proximal muscle starts wasting
Easy brushing and poor wound healing
List some effects cushings syndrome has on bone
Avascular necrosis
Osteoporosis
When are immunosuppressants used
- Organ transpant
- Bone marrow transplan t
- Autoimmune condition s
- Inflammatory bowel disease
- Oral medicine
Name soem common immunosuppressants
- azathioprine,
- mycophenolate mofetil,
- ciclosporin
- tacrolimus
but many others exist
List some problems with immunosuppressants
- Increased risk of infection 2. Diminished wound healing
- Increased risk of tumours especially lymphomas
What is azathioprine
A synthetic purine along used as an immunosuppressants
It is a prodrug of mercaptopurine
azathioprine is C________
Cytotoxic
As azathioprine is cytotoxic what does it do
It inhibits both cell mediated and antibody mediated immune reposted and inhibits clonal proliferation of both t and B cells
What does azathioprine do
- Inhibits both cell mediated and antibody mediated immune reposted and inhibits clonal proliferation of both t and B cells
- Inhibits purine synthesis and DNA synthesis
- Incorporates into your DNA to modify gene expression and has anti proliferation effects
How is azathioprine broken down
Broken down by the enzyme TPMT
What must we check before prescribing a patient azathioprine
Their TPMT levels
What is there an increased risk of in patients taking azathioprine
Increased risk of malignancy including that of the skin gastrointestinal tract and haematogenous malignancies such as lymphoma
What must you advice a patient taking azathioprine
- To avoid the sun due to increased skin cancer risk
- To have Annual flu and pneumococcal vaccines
What is mycophenolate mofetil
It is an cytotoxic steroid used as an immunosuppressants
Is a prodrug of myphenolic acid
State a key difference between mycophenolate mofetil and azathioprine
mycophenolate mofetils is more lymphocyte selective than azathioprine so has a narrower spectrum of activity
What do we mean by prodrug of myphenolic acid
It is a reversible inhibitor of inosine monophosphate dehydrogenase
What does mycophenolate mofetil do
- selectively inhibits synthesis of guanosine which inhibits proliferation of B and T cells
- inhibit leucotriene recruitment to sites of inflammation
When is mycophenolate mofetil contraindicated
In pregnancy or breast feeding women
Why is mycophenolate mofetil contraindicated in breast feeding and pregnant women
as it is toxic to foetuses as it selectively inhibits synthesis of guanosine which inhibits proliferation of B and T cells
When is mycophenolate mofetils used
- Organ transpant rejection
- SLE
- Haemolytic anaemia
- Mucous membrane pemphigoid,
- pemphigus,
- scleroderma,
- GVHD,
8.Crohn’s disease
What are the adverse effects of mycophenolate mofetil
- Bone marrow suppression
- Gastrointestinal disturbances
- risk on non melanoma skin cancers
- Gastrointestinal cancer and lymphoma
What is cyclosporin
A cyclic 11 amino acid polupeptide
What do calcineurin inhibitors do
They prevent activation of T cells and binds to proteins which then inhibit calcineurin to bring its clinical effects
What are the clinical effects of calcineurin inhibitors
- Inhibition of calcineurin activates transcription factors that stimulate IL-2
2, reduces IL-2 production of cytotoxic (Tc) and cytokine-producing Th1 cells - Also inhibits Th2-dependent B-cell response
What does calcineurin do
Activated T cells to produce il-2 AND other pro inflammatory cytokines
Inhibits mast cell degranulation and histamine release
What are calcineurin inhibitors metabolised by
P450 cytochrome chain of enzymes
What is Tacrolimus
macrolide antibiotic used systemically as an anti-rejection agent or topically in oral disease to treat severe or refractory inflammatory mucosal disease
What are red adverse effects of ciclosporin
- Nephrotoxicity (a high risk of this)
- Hypertension (a marked problem)
- Hepatotoxicity
- Gingival hyperplasia
- Increased risk of malignancies eg non melons skin cancers
What are red adverse effects of tacrolimus
- Nephrotoxicity (a high risk of this)
- Hypertension (a marked problem)
- Hepatotoxicity
- Increased risk of malignancies eg non melons skin cancers