Immunosuppression Flashcards
What is immunosuppression?
Immunosuppressive drugs dampen the effects of the immune system - T and B lymphocytes.
Give examples of these types of drugs used in renal medicine:
- Corticosteroids
- Calcineurin inhibitors
- Antimetabolites
- Monoclonal antibodies
- Proliferation inhibitors
- Corticosteroids
- Prednisolone
- Methylprednisolone
- Calcineurin inhibitors
- Ciclosporin
- Tacrolimus
- Antimetabolites
- Azathioprine
- MMF
- Monoclonal antibodies
- Alumtuzumab
- Basiliximab
- Proliferation inhibitors
- Sirolimus
What is the mechanism of action of prednisolone?
- Glucocorticoids suppress the immune system in numerous ways.
- They interfere with the function of multiple cell types inluding T cells.
- Most of the immunosuppressive actions of glucocorticoids are due to the alteration of transcription of numerous genes in leukocytes (up regulation and down regulation).
- After binding to the glucocorticoid receptor, the complex translocates into the nucleus and regulate gene transcription.
- Decreased T-cell production of IL-2 and IFN-γ.
- Decreased activation and migration of immune cells.
- Decreased monocyte production of IL-1 and TNF-α.
What are the contraindications and cautions for prednisolone?
- Congestive heart failure
- Diabetes mellitus
- Diverticulitis
- Glaucoma
- Steroid myopathy
- TB
- Hypertension
- Osteoporosis
- Peptic ulcer
- Psychiatric reactions
What are the endocrine adverse effects of prednisolone?
- Adrenal insufficiency
- Weight gain
- DM (or worsening of blood glucose control)
What are the possible effects on mood and behaviour from prednisolone use?
- Confusion
- Irritability
- Delusions
- Suicidal ideation
- Euphoria
- Insomnia
- Mood lability
- Psychotic reactions
- Behavioural disturbances
- Prescribe with care in those predisposed to psychiatric reactions.
What are the gastrointestinal adverse effects of prednisolone?
- Peptic ulceration with perforation and haemorrhage
- Dyspepsia
- Abdominal distension
What are the MSK adverse effects of prednisolone?
- Osteoporosis
- Proximal myopathy
What are the skin adverse effects of prednisolone?
- Thinning of the skin
- Easy bruising
- Delayed wound healing
What are the adverse effects of prednisolone on the eyes?
- Glaucoma
- Cataract
- Blurred vision
What is the main cardiovascular adverse effect of prednisolone?
Hypertension
What are the general adverse effects of prednisolone?
- Immunosuppression
- Cushing’s syndrome
What effect does long-term use of prednisolone have on infection risk?
- Long-term use increase susceptibility to infections and severity of infections.
- Clinical presentation of infections may also by atypical:
- Chicken pox
- Measles
What effect does prednisolone have on the function of the adrenal glands?
- Long-term treatment leads to adrenal atrophy.
- Stopping steroid therapy abruptly can lead to adrenal insufficiency.
- People on prolonged corticosterois treatment can have a blunted adrenocortical response to stress of any kind - doses of steroid should be incresed in:
- Significant intercurrent illness
- Trauma
- Surgical procedure
What should patients be prescribed alongside prednisolone?
-
Bone protection
- Calcium supplementation
- Vitamin D supplementation
What is the mechanism of action of tacrolimus?
- Major effect on T cells, though also has an effect on other cell types.
- Calcineurin is a protein phosphatase that works to activate T cells.
- It activates transcription factor (NFAT) by dephosphorylation.
- The activated NFAT is then translocated into the nucleus, where it upregulates the expression of IL-2.
- IL-2 stimulates the growth and differentiation of T cells.
What are the indications for use of tacrolimus?
- Topical use - atopic eczema / psoriasis
- Solid organ transplants
- Nephrotic syndrome - minimal change disease
- Oral tacrolimus products: prescribe and dispense by brand name only, to minimise the risk of inadvertent switching between products, which has been associated with reports of toxicity and graft rejection.
Describe the therapeutic drug monitoring associated with tacrolimus.
- Narrow therapeutic index
- High level of variability in the blood concentration of the drug between patients.
- Several drug interactions that affect CNI levels.
- Initial dosing - maintenance doses should be adjusted according to concentration in the blood.
What are the adverse effects of tacrolimus?
- Increased risk of infection
- Abnormal sensation
- Skin reactions
- Neoplasm
- Diabetes mellitus
- Headache
- Hypertension
- Nausea
- Peripheral neuropathy
- Renal impairment
- Sleep disorders
- Tremor
What is the mechanism of action of mycophenolate mofetil (MMF)?
- MMF interferes with purine synthesis - and therefore DNA synthesis - in T cells and B cells.
- Purines can either be synthesised de novo or they can be salvaged from free nucleotides - lymphocytes rely on the former mechanism, unlike other cells.
- Mycophenolic acid inhibits IMPDH, an enzyme essential to the de novo synthesis purines.
- So inhibition of DNA replication in T cells and B cells is selective.
What are the main indications for prescribing MMF?
- Solid organ transplants
- SLE / vasculitis
What are the contraindications / cautions when prescribing MMF?
- Active serious GI disease
- Elderly
- Increases susceptibility to skin cancer
List some common adverse effects of MMF.
- Anaemia
- Bone marrow disorders
- Diarrhoea
- GI disorders
- Thrombocytopaenia
