Eicosanoids, NSAIDs, DMARDs

Question 1

What the hell is a DMARD?

Answer 1

Disease Modifying Anti-Rheumatic Drug

Question 2

What is the precursor of eicosanoids and where is this released from?

Answer 2

Arachidonic acid, released from membrane via phospholipase A2

Question 3

What do COX1 / COX2 do?

Answer 3

They catalyze the oxygenation and peroxidation of arachidonic acid

Question 4

Where are COX1 / COX2 expressed?

Answer 4

COX1: expressed constitutively everywhere, especially in stomach and platelets

COX2: inducible form, present in inflammatory tissues but constitutive in kidney / vascular endothelium

Question 5

Which COX is the major source of prostanoids in inflammation and cancer?

Answer 5

COX2

Question 6

Which major eicosanoids are vasodilators vs vasoconstrictors?

Answer 6

Vasodilators: PGE2 and PGI2 (prostacyclin)
Vasoconstrictors: TXA2 (thromboxane) - contract SM

Overall, tend to favor causing vasodilation of blood vessels and hypotension

Question 7

What is the function of prostaglandins in the stomach?

Answer 7

Maintain secretion of mucins and limit pepsin / acid secretion (inhibition of COX1 causes GI distress / ulcer formation)

COX2 is needed to help existing ulcers heal

Question 8

What is the CNS effect of prostaglandins?

Answer 8

Pyrogenic and sensitizes nerve endings of pain fibers

Question 9

What does PGE2 do to the uterus?

Answer 9

Causes contraction

Question 10

What is the most likely explanation of anti-inflammatory effect of COX-inhibitors?

Answer 10

Diminished eicosanoid effects of vasodilation and sensitization of nociceptive nerves

Question 11

What can be used to treat pulmonary hypertensions?

Answer 11

Prostacyclin and epoprostenol and Iloprost

PGI2 analogs which are vasodilators

Question 12

What is alprostadil used for?

Answer 12

Maintaining patent ductus arterosus during caridac surgery

Question 13

What is the first prostanoid used for glaucoma?

Answer 13

Latanoprost - long-acting derivative of PGF2alpha, increased corneal aqueous humor outflow

Question 14

What are lipoxygenases and generally what do the products do? Do NSAIDs inhibit this?

Answer 14

Family of enzymes catalyzing oxygenation of arachadonic acid to hydroperoxides called “Leukotrienes”.

Products are chemoattractants for immune cells, which play a role in asthma and inflammatory bowel disease

NO-> NSAIDs are just COX inhibitors

Question 15

What is the mechanism of action of aspirin?

Answer 15

Inhibits COX1 and COX2, but preferentially COX1 by irreversibly acetylating the active site.

Question 16

What are the four main effects of aspirin?

Answer 16

1. Analgesia
2. Antipyresis
3. Anti-inflammation
4. Antithrombotic

Question 17

How is aspirin antithrombotic?

Answer 17

Inhibits the COX1 expressed in platelets, which would primarily be used to synthesize thromboxanes for platelet aggregation.

It has less of an effect on COX2 which is responsible for vasodilating the endothelium

Generally, this increases clotting time and reduces MI risk / anginal attacks

Question 18

What are two big risks of using aspirin? What are the mechanisms?

Answer 18

1. Gastric irritation, bleeding, and activation of peptic ulcers by inhibition of gastric COX1
2. Precipitation of gouty attacks (due to inhibition of uric acid secretion by kidney)

Question 19

How does acetaminophen work and why is it not considered an NSAID?

Answer 19

Nonspecific COX inhibitor which is not actually irritating to the stomach (probably because COX2 > COX1)

Analgesic and antipyretic, but not an NSAID because it does not have anti-inflammatory or anti-coagulant effects

Question 20

What are the mechanisms of action of ibuprofen and naproxen and how do they differ?

Answer 20

Non-selective REVERSIBLE COX inhibitors, probably greater COX2 activity so they have somewhat less GI side effects than aspirin.

Naproxen just has a longer halflife (Aleve)

Question 21

What are the common issues with ibuprofen use and why should you not take it with low-dose aspirin?

Answer 21

acute renal failure, interstitial nephritis, nephrotic syndrome.

Should not be taken with aspiring because it may ANTAGONIZE the cardioprotection offered by low dose aspirin (Cox-2 inhibition by ibuprofen disallows vasodilation via vascular endothelium)

Question 22

What are the indications of indomethacin? Why?

Answer 22

1. Gout
2. Ankylosing spondylitis
3. Pericarditis
4. Pleurisy / pleuritis
5. Patent ductus arteriosus

Not used often due to it being VERY powerful

Question 23

What are the side effects of indomethacin?

Answer 23

Severe gastric effects, thrombocytopenia, aplastic anemia, hyperkalemia (kidneys), coronary artery constriction

Question 24

What is Celecoxib? Why would it be used?

Answer 24

A reversible COX-2 inhibitor

About as good as non-selective inhibitors, but might be used because of lower incidence of gastric irritation

Question 25

When is misoprostol used? Why rarely used?

Answer 25

In concurrence with an non-selective NSAID as a synthetic prostaglandin which can prevent gastric ulcers. Rarely used due to severe diarrhea (like magnesium lul) and cannot be used during pregnancy (induction of labor)

Question 26

What do all NSAIDs do to the kidneys?

Answer 26

Decrease renal blood flow, cause fluid retention, and may cause hypertension / renal failure

Question 27

What are DMARDs used?

Answer 27

They suppress the proliferation and activity of lymphocytes and PMNs which reduce the inflammation, joint destruction, and slow the progression of rheumatoid arthritis

Question 28

What is the first line drug for RA and what is it often used with?

Answer 28

Methrotrexate -> causes thymidine deficiency Used in combination with Leflunomide (also reduces pyrimidine synthesis, but can cause serious liver disease)

Question 29

What is the mechanism of action of leflunomide?

Answer 29

Reduction of pyrimidine synthesis by inhibition of dihydroorotate dehydrogenase

Question 30

Why is hydroxychloroquine useful in rheumatoid arthritis?

Answer 30

It is a basic drug that accumulates in lysosomes of immune cells and phagocytes (like amoeba and protozoans) and inhibits chemotaxis, phagocytosis, and superoxide production of PMNs.

Question 31

What particular patient populations is hydroxychloroquine useful in?

Answer 31

Useful in pregnant patients since methotrexate, leflunomide and cyclophosphamide are all teratogens DO NOT USE in G-6-P DH Deficiency

Question 32

When are TNF inhibitors used for RA?

Answer 32

In moderate to severe disease, since they are more effective than methotrexate in reducing symptoms

Question 33

What are the three main TNF scavengers / inactivators? Main side effect?

Answer 33

1. Etanercept 2. Imflixima 3. Adalimumab Side effect is could cause TB if latent

Question 34

How does etanercept work?

Answer 34

Enbrel - fusion protect which puts the human TNF receptor on the Fc fragment of IgG, works by scavenging TNF

Question 35

How does abatacept work? When is it used?

Answer 35

Binds CD80 / CD86 on APCs to prevent T-cell activation via CD28 Used when anti-TNF agents are not working

Question 36

How does Rituximab work? When is it used?

Answer 36

Binds to B-cell receptor CD20 and causes apoptosis. This is expressed from the pre-B cell stage Used when anti-TNF agents are not working

Question 37

Can anti-TNF agents be used as a monotherapy, and what do you do if one doesn't work?

Answer 37

They can, but generally better to use in conjunction with methotrexate If one doesn't work, you can switch to another anti-TNF which may work, or a non-TNF biological agent like abatacept or rituximab