S8: immunosuppressants & NSAIDs

Question 1

Describe rheumatoid arthritis

Answer 1

Inflammatory change and proliferation of synovium leading to dissolution of cartilage and bone
Increase of pro-inflammatory substances compared to anti-inflammatory substances

Question 2

Describe the treatment strategy of rheumatoid arthritis

Answer 2

Early use of disease-modifying drugs 
Aim to achieve good disease control 
Use of adequate dosages 
Use of combinations of drugs
Avoidance of long-term corticosteroids

Question 3

Describe the treatment strategy of SLE and vasculitis

Answer 3

Symptomatic relief
Reduction in mortality
Prevention of organ damage
Reduction in long term morbidity caused by disease & by drugs

Question 4

Describe the mechanism of action of corticosteroids

Answer 4

Prevent interleukin IL-1 and IL-6 production by macrophages

Inhibit all stages of T-cell activation

Question 5

List indications for azathioprine

Answer 5

SLE & vasculitis – maintenance therapy
Inflammatory bowel disease
Other uses include use as ‘steroid sparing’ drug

Question 6

Describe the mechanism of action of azathioprine

Answer 6

Cleaved to 6-MP, which is converted to TIMP

-decreases DNA and RNA synthesis

Question 7

Outline the adverse effects of azathioprine

Answer 7

Bone marrow suppression
Increased risk of malignancy
Increased risk of infection
Hepatitis

Question 8

List examples of calcineurin inhibitors

Answer 8

Ciclosporin

Tacrolimus

Question 9

List indications and contraindications for calcineurin inhibitors

Answer 9

Widely used in transplantation
Also atopic dermatitis & psoriasis
Not often used in rheumatology – renal toxicity (check BP & eGFR regularly)
Drug interactions with CYP450 drugs

Question 10

Describe the mechanism of action of calcineurin inhibitors

Answer 10

Active against helper T cells

Prevent production of IL-2 via calcineurin inhibition

Question 11

List indications for mycophenolate mofetil

Answer 11

Used primarily in transplantation
Good efficacy as induction and maintenance therapy for lupus nephritis
Maintenance therapy for vasculitis

Question 12

Describe the mechanism of action and adverse effects of mycophenolate mofetil

Answer 12

Prodrug
Inhibits inosine monophosphate dehydrogenase, which impairs B and T cell proliferation
Adverse effects: nausea, vomiting, diarrhoea & myelosuppression

Question 13

Describe cyclophosphamide

Answer 13

Alkylating agent – cross links DNA so that it cannot replicate
Suppresses T and B cell activity
Indications: lymphoma, leukaemia, solid cancers, lupus nephritis

Question 14

Describe adverse effects of cyclophosphamide

Answer 14

Increased risk of bladder cancer, lymphoma & leukaemia
Infertility
Adjust dose in renal impairment
(mycophenolate mofetil safer & as effective in lupus nephritis)

Question 15

List indications for methotrexate

Answer 15

Gold standard treatment for RA

Other indications: malignancy, psoriasis & Crohn’s disease

Question 16

Describe the mechanism of action of methotrexate in malignancy & as a DMARD

Answer 16

In malignancy – inhibit dihydrofolate reductase -> reducing FH4 needed for DNA and protein synthesis
DMARD – inhibition of inflammatory mediators, T cells and adenosine

Question 17

List adverse effects of methotrexate

Answer 17

Mucositis, marrow suppression (both respond to folic acid supplementation)
Hepatitis, cirrhosis, pneumonitis, infection risk
Highly teratogenic, abortifacient

Question 18

Describe sulfasalazine

Answer 18

Relieve pain, stiffness & fights infection
Inhibition of T cell and neutrophil activity
Release 5-aminosalicylic acid (5-ASA) – immunosuppressive

Question 19

Outline adverse effects of sulfasalazine

Answer 19

Myelosuppression, hepatitis, rash
Milder side effects: nausea, abdo pain/vomiting
Very few drug interactions & safe in pregnancy

Question 20

Describe biologicals

Answer 20

Monoclonal antibodies made specifically to block any given substance in the body or to target any specific cell type
Act by TNF-alpha inhibition
ADR: test for latent TB as inhibition of TNF-alpha may reactivate latent disease (TNF is essential in granuloma formation so that TB bacilli are walled off)
Caution with other immunosupressants
Eg. infliximab, golimumab & adalimumab

Question 21

Describe rituximab

Answer 21

Causes B cell apoptosis – binds specifically to a unique cell-surface marker CD20
Very effective in RA

Question 22

Describe prostanoids

Answer 22

Prostanoids = prostaglandins, prostacyclin & thromboxanes (PGE2, PGF2a, PGD2, PGI2 & TXA)
Produced locally on demand – different enzymes, different prostanoids, short half lives so fine local control
Act locally at GPCRs & action is often enhanced by local autacoids including bradykinin and histamine
TXA2 and PGI2 have apposing vascular effects; imbalance to prostanoids plays significant role in hypertension, MI and stroke risk

Question 23

Describe arachidonic acid and prostanoid synthesis

Answer 23

Arachidonic acid derived primarily from dietary linoleic acid – incorporated into phospholipids
Found throughout the body – particularly in muscle, brain, liver & kidney

Question 24

Describe PGE2 and gastric acid secretion

Answer 24

PGE2 contributes to regulation of acid secretion in parietal cells
Prostacyclin contributes to maintenance of blood flow and mucosal repair

Question 25

Describe cyclooxygenase enzymes

Answer 25

COX-1: constitutively active across most tissues | COX-2: inducible in chronic inflammation, constitutively in brain, kidney and bone

Question 26

List homeostatic functions of COX-1 and COX-2

Answer 26

COX-1: GI protection, platelet aggregation & vascular resistance COX-2: renal homeostasis, tissue repair and healing, reproduction & inhibition of platelet aggregation

Question 27

List pathological functions of COX-1 and COX-2

Answer 27

COX-1: chronic inflammation, chronic pain & raised BP | COX-2: chronic inflammation, chronic pain, fever, blood vessel permeability

Question 28

Describe NSAIDs

Answer 28

Have antipyretic, analgesic and anti-inflammatory properties Mode of action: inhibition of COX -> decreased prostaglandin, prostacyclin & thromboxane synthesis Compete with arachidonic acid for hydrophobic site of COX enzymes

Question 29

Describe the analgesic action of NSAIDs

Answer 29

Local peripheral action at site of pain Inhibition reduces peripheral pain fibre sensitivity by blocking PGE2 Decreased PGE2 synthesis in dorsal horn -> decreased neurotransmitter release -> decreased excitability of neurones in pain relay pathway Full analgesia after several days dosing

Question 30

Describe the anti-inflammatory action of NSAIDs

Answer 30

NSAIDs reduce production of prostaglandins released at site of injury Symptomatic relief with COX inhibition – little effect on underlying chronic condition

Question 31

Describe the antipyretic action of NSAIDs

Answer 31

Inhibition of hypothalamic COX-2 where cytokine induced prostaglandin synthesis is elevated Results in a reduction in temperature

Question 32

Describe COX selectivity of NSAIDs

Answer 32

Differentiated by their selectivity COX-2 selective compounds inhibit COX-2 with much greater selectivity than COX-1 at therapeutic doses Aspirin, ibuprofen, naproxen, diclofenac, celecoxib, etericoxib (increasing COX-1 selectivity -> increasing COX-2 selectivity)

Question 33

What are the adverse effects, warnings, contraindications & important drug interactions of NSAIDs? (GI system)

Answer 33

Adverse effects: dyspepsia, nausea, peptic ulceration, bleeding and perforation, exacerbation of IBD -decreased mucus & bicarbonate secretion, increased acid secretion -decreased mucosal blood flow -> enhanced cytotoxicity and hypoxia Warnings: elderly, prolonged use, smoking, alcohol, history of peptic ulceration, H. pylori Important drug interactions: aspirin, glucocorticoid steroids, anticoagulants

Question 34

What are the adverse effects, warnings, contraindications & important drug interactions of NSAIDs? (renal)

Answer 34

Adverse effects: reversible decrease in GFR & decrease renal blood flow, increased BP due to inhibition of prostaglandins Warnings, contraindications: underlying CKD, heart failure Important drug interactions: ACEi, ARBs, diuretics

Question 35

Describe selective COX-2 inhibitors

Answer 35

Less GI ADRs, renal ADRs similar to non-selective Do not share antiplatelet action but inhibit PGI2 Can be useful when monitored in severe osteo and rheumatoid arthritis for longer term treatment (NB: ALL NSAIDs increase risk of MI)

Question 36

List examples of selective COX-2 inhibitors

Answer 36

Celecoxib | Etoricoxib

Question 37

Describe NSAIDs and protein binding

Answer 37

Displace other bound drugs -> increases free drug concentration -sulfonylurea: hypoglycaemia -methotrexate: accumulation and hepatotoxicity -warfarin: increased risk of bleeding Competitive displacement of some other drugs – likely dose adjustment needed & increased monitoring

Question 38

List indications for NSAID use

Answer 38

``` Inflammatory conditions Osteoarthritis Postoperative pain Topical use on cornea Menorrhagia ```

Question 39

Describe paracetamol

Answer 39

Antipyretic action, use for mild to moderate analgesia and fever At therapeutic doses generally well tolerated with fewer common ADRs COX-2 selective inhibition in CNS – decrease pain signals to higher centres Very little anti-inflammatory action

Question 40

Describe NAPQI

Answer 40

Highly reactive metabolite At normal therapeutic doses, conjugation with glutathione renders NAPQI harmless When hepatic glutathione is limited, NAPQI causes cell death by necrosis and apoptosis

Question 41

Describe paracetamol overdose

Answer 41

Can be asymptomatic for many hours First: nausea, vomiting, abdominal pain; maximal liver damage occurs at 3-4 days Treatment: glutathione thiol replacement – i.v. N-acetylcysteine Can’t give glutathione itself because it can’t get into the hepatocytes

Question 42

List mechanisms by which NSAIDs can cause GI adverse drug reactions

Answer 42

Decreased mucus secretion Decreased bicarbonate secretion Reduced mucosal blood flow pH partitioning & accumulation of NSAID at gastric mucosa -inhibition of PGE2 and PGI2 major factor in these ADRs

Question 43

Which prostanoids show apposing platelet aggregatory action?

Answer 43

PGI2 & TXA2 PGI2 inhibits platelet aggregation TXA2 contributes to platelet aggregation