Session 6 - Autoimmunity

Question 1

What is autoimmunity?

Answer 1

the state that is present when an individual has made an immune response to self-antigens.

Question 2

What can aid in the diagnosis of autoimmunity?

Answer 2

the presence of autoantibodies in serum provides evidence for autoimmunity, and these may be helpful in diagnosing and monitoring autoimmune diseases.

Question 3

What does autoimmune disease mean?

Answer 3

the term applied to a disease in which autoimmunity is thought to play a significant pathogenic role.

Question 4

What are two overall categories of autoimmune disease?

Answer 4

Organ specific (target antigen in one specific tissue) vs Non-organ specific (if target antigen in many different tissues)

Question 5

Give some organ specific autoimmune diseases

Answer 5

Hashimoto’s
Thyrotoxicosis
Primary myxoedema
Chronic atrophic gastritis
Pernicious anaemia
Addison’s Disease
Myasthenia gravis
Diabetes mellitus (type 1)
Premature ovarian failure
Male infertility

Question 6

Give some mixed autoimmune diseases

Answer 6

Goodpasture’s syndrome
Primary biliary cirrhosis
Autoimmune haemolytic disease
Ulcerative colitis

Question 7

Give some non-organ specific immunse diseases

Answer 7

Systemic Lupus Erythematosus
Rheumatoid arthritis
Sjogren’s syndrome
Progressive systemic sclerosis

Question 8

Name some immunosupressant categories of drugs

Answer 8

Glucocorticoids
Azathiporine
Cytotoxic alkylating agents
Calcineurin inhibitors 
Mycophenolate mofetil

Question 9

What is the mechanism of action of glucocorticoids

Answer 9

 Diffuse into cytoplasm and bind receptor. Complex moves to nucleus and binds Hormone Response Element (HRE). Inducers/Inhibits transcription.

Question 10

Give three examples of glucocorticoids

Answer 10

 Prednisolone (Oral)
 Beclometasone (Topical/Inhaled)
 Hydrocortisone (Cortisol) (Oral for replacement, IV for status asthmaticus and anaphylactic shock)

Question 11

What are the indications for glucocorticoids?

Answer 11

 Immunosuppression
 Anti-inflammatory therapy
 Replacement of endogenous corticosteroids

Question 12

What are the contraindications for glucocorticoids?

Answer 12

Systemic infection

Question 13

Give five adverse drug reactions of glucocorticoids

Answer 13

	Cushingoid effects
	Suppression of HPA axis
	Osteoporosis
	Suppression of growth in children
	Mineralocorticoid effects if the glucocorticoid also has those actions

Question 14

Why should long term therapy with glucocorticoids be withdrawn slowly?

Answer 14

 Long term therapy must be withdrawn slowly, due to HPA suppression

Question 15

What is the mechanism of action of azathioprine?

Answer 15

 Azathioprine is a pro-drug, which is converted into 6-Mercaptopurine in the liver
 6-Mercaptopurine is a fraudulent purine nucleotide that impairs DNA synthesis and has a cytotoxic action on dividing cells

Question 16

What are four indications for azathioprine?

Answer 16

 Rheumatoid Arthritis, Inflammatory Bowel Disease
 Prevention of graft and transplant rejection
 Autoimmune conditions where corticosteroid therapy alone inadequate
 Leukaemia

Question 17

What is the route of administration for azathioprine?

Answer 17

 Oral / IV

Question 18

What are three adverse drug reactions for azathioprine?

Answer 18

 Myelosuppression  Leukopenia, thrombocytopenia, anaemia
 Increased infection susceptibility
 GI disturbances (nausea, vomiting, diarrhoea)

Question 19

Give a drug interaction with azathioprine

Answer 19

 Interacts with Allopurinol (treats gout), necessitates lowering of dose

Question 20

Give a therapeutic note for the use of azathioprine

Answer 20

 6-Mercaptopurine is eliminated by the enzyme TPMT, which is subject to a high rate of genetic polymorphism. High levels of TPMT expression will lead to under-treatment, low levels of TPMT expression gives toxicity.

Question 21

What is the mechanism of action of cytotoxic alkylating agents

Answer 21

 Pro-drug, that is activated by CYP450s.
 Alkylating agent, which creates cross-links in DNA so that it cannot replicate. Therefore it selectively acts on cells with a higher mitotic rate.

Question 22

Give a cytotoxic alkylating agent

Answer 22

 Cyclophosphamide

Question 23

Give an indication for cytotoxic alkylating agents

Answer 23

 Immunosuppression

 Cancer chemotherapy

Question 24

Give a contraindication for cytotoxic alkylating agents

Answer 24

 Pregnancy

Question 25

Give an adverse drug reaction for cytotoxic alkylating agents

Answer 25

 Induction of bladder cancer (urine concentration of acrolein metabolite)  Lymphoma and Leukaemia  Infertility & Teratogenesis

Question 26

Give a drug-drug intteraction for cytotoxic alkylating agents

Answer 26

 Pro-drug is activated by CYP450s (inducers/inhibitors)

Question 27

What is the mechanism of action of Calcineurin Inhibitors

Answer 27

 Reduction in IL-2 synthesis and release, via Calcineurin inhibition suppressing both cell-mediated and antibody-specific adaptive immune responses. Active against T helper cells.  Ciclosporin binds to Cyclophilin and Tacrolimus binds to Tacrolimus-Binding-Protein  Drug/Protein complexes bind to and inhibit Calcineurin, which normally has a phosphatase activity on the Txn factor for IL-2. Therefore, inhibition of Calcineurin reduces IL-2

Question 28

What is the indication for Calcineurin Inhibitors

Answer 28

 Prevention of graft and transplant rejection  Prevention of graft vs. host disease  Atopic dermatitis, psoriasis

Question 29

Give two calcineurin inhibitors

Answer 29

 Cyclosporin (Binds Cyclophilin) |  Tacrolimus (Binds Tacrolimus-Binding-Protein)

Question 30

Give three adverse drug reactions of calcineurin inhibitor

Answer 30

 Nephrotoxic (proximal tubule), renal damage almost always occurs  Hypertension in 50% of people  GI disturbances

Question 31

What is a drug-drug interaction of calcineurin inhibitor ?

Answer 31

 Metabolism is by CYP450, so is affected by inducers/inhibitors

Question 32

Give a therapeutic note for calcineurin inhibitoprs

Answer 32

 Unlike most immunosuppression agents, Cyclosporin does not cause myelosuppression

Question 33

What is an indication for Mycophenolate Mofetil

Answer 33

 Transplant immunosuppression (agent of choice)

Question 34

What is a mechanism of action for Mycophenolate Mofetil

Answer 34

 Inhibits the enzyme Inosine Monophosphate Dehydrogenase, which is required for Guanosine synthesis  Impaired B-cell and T-cell proliferation

Question 35

What is an adverse drug reaction for Mycophenolate Mofetil

Answer 35

 Myelosuppression  Leukopenia, neutropenia |  Increased risk of infection (especially viral)

Question 36

What is a therapeutic notes for mycophenolate mofetil

Answer 36

 Highly selective. Spares other rapidly dividing cells, due to the presence of guanosine salvage pathways

Question 37

Name a couple disease modifying anti-rheumatic drugs (DMARDS)

Answer 37

Methotrexate Aminosalicylates Anti-TNF agents

Question 38

Give an indication for methotrexate use

Answer 38

 Immunosuppression and Cancer chemotherapy

Question 39

Give a contraindication for methotrexate

Answer 39

 Pregnancy

Question 40

Give four routes by which methotrexate can be administered

Answer 40

 Orally, intravenously, intramuscularly, intrathecally

Question 41

What is the mechanism of action for methotrexate?

Answer 41

 Antifolate  Competitively antagonises Dihydrofolate Reductase (DHFR), preventing the regeneration of intermediates (tetrahydrofolate) essential for the synthesis of purines and thymidine, thus inhibiting DNA synthesis.

Question 42

What is an adverse drug reaction to methotrexate? (5)

Answer 42

```  Mucositis  Myelosuppression  Hepatitis, cirrhosis  Increased infection risk  Teratogenesis ```

Question 43

Give a drug-drug interaction for methotrexate

Answer 43

 Adverse DDIs with drugs affecting renal blood flow and renal elimination, e.g. NSAIDs

Question 44

What clinical monitoring should be carried out while on methotrexate?

Answer 44

 Baseline chest X-ray, FBC, LFT, U+E + Creatinine |  Monthly FBC, LFT, U+E + Creatinine

Question 45

What should you be worried about if giving methotrexate with NSAIDs?

Answer 45

 Plasma protein binding ~50% - NSAIDs displace, raising plasma concentration

Question 46

How often is methotrexate given?

Answer 46

Weekly

Question 47

What do aminosalicylates treat,and how?

Answer 47

 Rheumatoid arthritis  Inflammatory bowel conditions  Sulfasalazine is broken down in the gut to the active component 5-aminosalicylate (5-ASA) and sulfapyridine, which acts as a vehicle to transport the drug to the colon.  Inhibition of T-cell proliferation and IL-2 production. Reduced Neutrophil chemotaxis and degranulation.

Question 48

What are some contraindications for aminosalicylates?

Answer 48

 Renal impairment |  Hypersensitivity

Question 49

Give four adverse drug reactions of aminosalicylates

Answer 49

 Myelosuppression  Hepatitis  Rash  GI disturbances (Nausea, vomiting, abdominal pain)

Question 50

Name two anti-tnf agents

Answer 50

 Infliximab (Monoclonal Antibody) |  Etanercept (Fusion protein)

Question 51

Give a mechanism of action of tnf-a

Answer 51

 Blocks the effects of TNF-α |  Decreased inflammation, decreased Angiogenesis, decreased joint destruction

Question 52

Give an adverse drug reaction of anti-tnf (4)

Answer 52

 Increased infections  Tiredness, dizziness  Itching  GI disturbances

Question 53

Appreciate the pharmacological rationale for using Immunosuppressants in treating certain cancers

Answer 53

o Some immunosuppressants work by inhibiting the division of cells  E.g. Azathioprine, Methotrexate, Cyclophosphamide, Cyclosporin o Some cancers are the uncontrolled division of immune cells  Therefore immunosuppressants will work to suppress the cancer