Immunosuppressants

Question 1

What are some of the conditions that are treated with immunosuppressants?

Answer 1

Bone marrow/organ transplants
Autoimmune conditions

Question 2

What are the 5 types of immunosuppressants

Answer 2

Glucocorticoids
Immunophilin ligands
MMF
Cytotoxic agents eg. Methotrexate
Ig-based therapies

Question 3

What are DMARDs

Answer 3

Disease Modifying Anti-Rheumatic Drugs: stop/slow the disease process of inflam. forms of arthritis and CT disorders

Question 4

what are the DMARDs classifications

Answer 4

conventional: Metho, Hydroxychloroquine, Sulfasalazine: target entire immune system broadly

Biologic: target very specific steps in inflam. process

Question 5

How do Glucocorticoids suppress the immune system?

Answer 5

steroid enters the cell, binds to cytosolic receptors, changes gene transcription within the cell (eg. make less interleukin) and mRNA is then edited to produce different proteins

Essentially:
1. Decrease synthesis of prostaglandins, leukotrienes, cytokines

2. Inhibit prolif. of T-lymphs, cytotoxic to some T cells (impairs cell-mediated immunity)

Question 6

Clinical uses of glucocorticoids

Answer 6

Suppress immunological reactions after organ transplantation

Treatment of haematological cancers

Autoimmune diseases (RA, UC)

Asthma/COPD: reduce inflam.

Question 7

Adverse effects associated with longterm glucocorticoid use?

Answer 7

ADRENAL SUPPRESSION (inhibition of HPA axis-prolonged use of steroids (more than 2 weeks), abrupt withdrawal can lead to adrenal crisis)

Behavioural changes: Insomnia

Cushings, Cataracts

Diabetes

Muscle wasting

Osteoporosis

Psychosis

Stunting, Salt retention

Question 8

What are three examples of immunophilin ligands?

Answer 8

Tacrolimus
Ciclosporin

these above two are calcineurin inhib

Sirolimus

Question 9

Clinical uses of immunophilin ligands

Answer 9

Prevent rejection following solid organ transplant

Prevents Graft versus Host Disease in stem cell transplant

Autoimmune conditions

Question 10

What are immunophilin ligands?

Answer 10

Immunophilins are small proteins found in cytoplasm of T cells
NB role in responses of t cells to activation and cytokine production

They work by binding to immunophilins to inhibit their activation of calcineurin

Question 11

How does Ciclosporine WORK?

Answer 11

Binds to cyclophilin:i nhibits calcineurin activation and reduce entry of NFAT into the nucleus and reduce prod. of cytokines that normally occurs in response to T cell activation

Question 12

How does Tacrolimus work?

Answer 12

Binds to FK-binding protein: inhibits calcineurin activation and reduce entry of NFAT into the nucleus and reduce prod. of cytokines that normally occurs in response to T cell activation

Question 13

What does Sirolimus bind to?

Answer 13

FK-binding protein

Question 14

Sirolimus MOA?

Answer 14

Essentially: interferes with prolif. of lymphs

Does not inhibit calcineurin but rather inhibits kinase activity of mTOR pathway which regulates growth and proliferation

inhibiting mTOR means that sirolimus effectively inhibits T cell proliferation in response to IL-2

Question 15

What are the respective formulations for the three immunophilin ligands

Answer 15

1. Ciclosporin and Tacrolimus: Oral and IV
2. Sirolimus: oral only

Question 16

PK of cyclosporin

Answer 16

Variable absorption: erratic bioavailability

Metabolised by CYP450

Victim of drug-drug interactions

Question 17

Is nephrotoxicity more common with ciclosporin or tacrolimus?

Answer 17

Ciclosporin

Hirsuitism
Gingival hyperplasia

Question 18

Tacrolimus specific side effects

Answer 18

Alopecia
More commonly hyperglycaemia

Question 19

Sirolimus side effects

Answer 19

Myelosuppression eg. thrombocytopaenia

Hyperlipidaemia
Hepatotoxicity
Diarrhoea

Question 20

Signs of toxicity in ciclosporin and tacrolimus use

Answer 20

Nephrotoxicity
HPT
Neurotoxicity
Hyperglycaemia
HyperK
Hyperlipid

Question 21

How does MMF work?

Answer 21

It is an antiproliferative

Cells need purines and pyrimidines for nucleic acid synthesis

there are two pathways to do this: De Novo and Salvage

De Novo pathway needs IMPDH to work.

MMF converts to MMA and this INHIBITS IMPDH, therefore, no purine can be made for DNA synthesis

T & B cells rely solely on this De Novo pathway, T cells can not proliferate and B cells can not produce antibody

Question 22

Clinical use of MMF

Answer 22

Liver, kidney, heart transplants

Combined with low dose cyclosporin to prevent nephrotoxicity (can use a lower dose of ciclosporin if combined with MMF)

Autoimmune (lupus nephritis)

Question 23

Signs of MMF toxicity

Answer 23

GIT disturbances

Myelosuppression

Question 24

What is an ideal transplant medication combination to suppress the immune system?

Answer 24

Use low doses of several drugs

Avoid over immunosuppression

Question 25

Cytotoxic Drugs MOA Eg. Methotrexate

Answer 25

Cytotoxic drug Inhibits Dihydrofolate reductase: reduced synthesis of purines and nucleic acids Suppresses inflammation and cell activity and replication Essentially:It acts at the level of the cell, destroying the cell itself by inhibiting the cell’s ability to synthesis proteins, divide and replicate (less T cell production)

Question 26

Clinical uses of methotrexate

Answer 26

Cancer: acute leukaemia, non-Hodgkin's lymphoma, solid tumours (sarcoma) via antiproliferative action Autoimmune: psoriasis, RA Haematopoietic stem cell transplantation Ectopic pregnancy

Question 27

Pharmacokinetics of Methotrexate

Answer 27

IV, oral route: good tissue distribution Bioavailability is saturable: oral bioavail. is erratic at moderate to high doses Metabolised in liver Elim. renally so need to adjust according to eGFR

Question 28

Methotrexate contraindications

Answer 28

Blood disorders (neutropaenia) Renal/Hepatic disease Herpes/Varicella infection (past and present) Serous effusions Pregnancy/lactation

Question 29

Adverse effects methotrexate

Answer 29

BM suppression Mucosal ulceration Derm: alopecia, rash, pigmentation, urticaria Liver and Renal Toxicity hyperuricaemia Pulm. pneumonitis

Question 30

Azathioprine: What is it and MOA

Answer 30

Cytotoxic drug Prodrug of mercaptopurine, which interferes with purine nucleic acid metabolism, disrupting DNA synthesis and T cell proliferation and is used in the management of rheumatic diseases and organ transplantation

Question 31

sulfasalazine MOA

Answer 31

Cytotoxic drug Interferes with activity of T-lymphs Inflam. bowel disease and RA

Question 32

Hydroxychloroquine MOA

Answer 32

Antimalarial drug also cytotoxic RA and SLE

Question 33

Cyclophosphamide MOA

Answer 33

alkylating agent that breaks DNA dont ask me how Leukaemia and lymphoma treatment

Question 34

Monoclonal Antibodies

Answer 34

TNF-A inhib: Infliximab, Adalimumab, Etanercept Anti-B cell antibody: Rituximab CD20 molecules on B cells IL-2 receptor inhibitors: Basiliximab High specificity

Question 35

Indications for Monoclonals

Answer 35

TNF-A inhib: RA, Psoriasis, Chrons Anti-B cell antibodies: RA, lymphoma IL-2 recep inhibitors: prevent organ rejection

Question 36

Issues associated with Monoclonals

Answer 36

Hypersensitivity Serum sickness Autoantibodies Infections: TNF-A INHIB CAUSE TB Cost