Anti-rheumatic drugs (DMARDs)

Question 1

List the relevant DMARDs used to treat RA

Answer 1

Methotrexate

Sulfasalazine

Gold compounds

Penicillamine

Chloroquine

Question 2

What are the main targets (generally) for DMARDs?

Answer 2

Preventing antigen-presenting cells from activating T cells

Preventing IL-2 activation of TNF-alpha

Preventing induction of cytotoxic T cells

Preventing activation of B cells

Preventing production of autoimmune antibodies

Impairing IL-1 action

Question 3

What is the MOA sulfasalazine?

Answer 3

Scavenging toxic oxygen metabolites produced by neutrophils

Inhibits T-cell proliferation and B-cell activation

Has a 5-aminosalicylic acid moeity that is a putative radical scavenger

Question 4

What are some notable ADRs of sulfasalazine?

Answer 4

GI disturbances, malaise, headaches

Skin reactions (reversible)

*Impairs folic acid absorption

Blood dyscrasia

Anaphylactic type reactions

Question 5

What is the MOA of gold compounds used in RA?

Answer 5

Unclear MOA = Auranofin (NOT AUROTHIOMALATE) inhibits induction of IL-1 and TNF-alpha

Helps ease pain and swelling, prevent progression of bone and joint disease

Question 6

How do gold compounds react/behave in the body? (pk, accumulation?, excretion?)

Answer 6

Oral form = auranofin; IM = sodium aurothiomalate

Gradually concentrates in tissue (liver, synovial, kidney tubules, adrenal cortex, macrophages)

Renally excreted but remains in tissue

Question 7

What are some notable ADRs of gold compounds?

Answer 7

skin rashes, mouth ulcers, flu-like sx

proteinuria, thrombocytopenia

Encephalopathy, peripheral neuropathy, hepatitis

Question 8

What is the MOA penicillamine?

Answer 8

Dec immune response, IL-1 generation, and/or partly by an effect on collagen synth

Question 9

Outline some key points of penicillamine pk (oral absorption? excretion?)

Answer 9

Only half of oral dose absorbed

Excreted in urine

Metal chelator, do not give w/ gold compounds

Question 10

Appearance of what penicillamine ADRs should result in cessation of therapy?

Answer 10

Bone marrow disorders (e.g. leucopenia, aplastic anaemia)

Autoimmune reactions (e.g. thyroiditis, myasthenia gravis)

Question 11

List some notable ADRs of penicillamine in RA

Answer 11

Occurs in 40% patients, dose dependent

Anorexia, fever, N/V, taste disturbances, rashes

Dose related thrombocytopenia

Question 12

Which DMARD can cause ocular toxicity?

Answer 12

hydroxychloroquine

Question 13

What is the MOA of methotrexate?

Answer 13

Inhibits dihydrofolate reductase –> prevent formation of active folate and addition of single carbon units to DNA base precursors

Impair B cells and T cells too

Question 14

What are some notable ADRs of methotrexate?

Answer 14

Blood dyscrasia (some fatal) - folic acid may minimise

Liver cirrhosis

GI toxicity

Stomatitis

C/I in pregnancy

Question 15

What is the MOA of azathioprine?

Answer 15

Metabolised to 6-mercaptopurine –> inhibits clonal proliferation during induction phase of the immune system by a cytotoxic action on dividing cells

Question 16

What are the notable ADRs of azathioprine?

Answer 16

Depression of bone marrow

N/V, skin, eruption, mild hepatotoxicity

Question 17

What is the MOA of leflunomide?

Answer 17

Relatively specific inhibitory effect on activated T cells

Its metabolite inhibits de novo synthesis of pyrimidines by inhibiting dihydroorotate dehydrogenase

Question 18

List some notable points about leflunomide pk (circulation? oral activity?)

Answer 18

Orally active, well absorbed from GIT

Long plasma half

Active metabolite teriflunomide = undergo enterohepatic circulation

Question 19

What are some notable ADRs of leflunomide?

Answer 19

Diarrhoea, alopecia

Raised liver enzymes (inc risk of hepatic failure)

Long half life = inc risk of cumulative tox

Foetal injury is used in preg

Question 20

List the main anti-cytokine drugs used in RA

Answer 20

Infliximab, adalimumab

Etanercept

Anakinra

Basiliximab and daclizumab

Question 21

What is the main target of infliximab and adalimumab?

Answer 21

Chimeric mouse/human monoclonal antibodies against TNF-alpha

Question 22

What is the main target of etanercept?

Answer 22

TNF receptor fused to the Fc domain of human IgG molecule

Question 23

What is the main target of anakinra?

Answer 23

IL-1 antagonist

Question 24

What is the main target of basiliximab and daclizumab?

Answer 24

monoclonal antibodies against alpha chain of the IL-2 receptor

Question 25

Outline some important facts about anticytokine pk (etanercept, inflix, adalim, anakinra)

Answer 25

Etanercept = subcut

Inflix = used w/ methotrexate, IV

Adalimumab = sc

Anakinra = sc daily

Question 26

What are some notable ADRs of the anticytokine drugs used in RA?

Answer 26

May precipitate latent disease or encourage opportunistic infections –> due to immunosuppressive properties (impact on immune cells)

Etanercept = Blood dyscrasias and demyelinating CNS disorders

Question 27

What is the MOA of tofacitinib?

Answer 27

Inhibits JAK protein –> prevents phosphorylation of STAT –> prevents translocation of STAT into the nucleus and activation of gene transcription

downregulates cytokine production

Question 28

What are some notable ADRs of tofacitinib?

Answer 28

Immune syst suppression (screen for TB. hep)

Elevated cholesterol

GI (diarrhoea, bowel perforation)

Lymphoma and other malignancies