Eicosanoids, NSAIDs, DMARDs Flashcards
What the hell is a DMARD?
Disease Modifying Anti-Rheumatic Drug
What is the precursor of eicosanoids and where is this released from?
Arachidonic acid, released from membrane via phospholipase A2
What do COX1 / COX2 do?
They catalyze the oxygenation and peroxidation of arachidonic acid
Where are COX1 / COX2 expressed?
COX1: expressed constitutively everywhere, especially in stomach and platelets
COX2: inducible form, present in inflammatory tissues but constitutive in kidney / vascular endothelium
Which COX is the major source of prostanoids in inflammation and cancer?
COX2
Which major eicosanoids are vasodilators vs vasoconstrictors?
Vasodilators: PGE2 and PGI2 (prostacyclin)
Vasoconstrictors: TXA2 (thromboxane) - contract SM
Overall, tend to favor causing vasodilation of blood vessels and hypotension
What is the function of prostaglandins in the stomach?
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
What is the CNS effect of prostaglandins?
Pyrogenic and sensitizes nerve endings of pain fibers
What does PGE2 do to the uterus?
Causes contraction
What is the most likely explanation of anti-inflammatory effect of COX-inhibitors?
Diminished eicosanoid effects of vasodilation and sensitization of nociceptive nerves
What can be used to treat pulmonary hypertensions?
Prostacyclin and epoprostenol and Iloprost
PGI2 analogs which are vasodilators
What is alprostadil used for?
Maintaining patent ductus arterosus during caridac surgery
What is the first prostanoid used for glaucoma?
Latanoprost - long-acting derivative of PGF2alpha, increased corneal aqueous humor outflow
What are lipoxygenases and generally what do the products do? Do NSAIDs inhibit this?
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
What is the mechanism of action of aspirin?
Inhibits COX1 and COX2, but preferentially COX1 by irreversibly acetylating the active site.
What are the four main effects of aspirin?
- Analgesia
- Antipyresis
- Anti-inflammation
- Antithrombotic
How is aspirin antithrombotic?
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
What are two big risks of using aspirin? What are the mechanisms?
- Gastric irritation, bleeding, and activation of peptic ulcers by inhibition of gastric COX1
- Precipitation of gouty attacks (due to inhibition of uric acid secretion by kidney)
How does acetaminophen work and why is it not considered an NSAID?
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
What are the mechanisms of action of ibuprofen and naproxen and how do they differ?
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)
What are the common issues with ibuprofen use and why should you not take it with low-dose aspirin?
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)
What are the indications of indomethacin? Why?
- Gout
- Ankylosing spondylitis
- Pericarditis
- Pleurisy / pleuritis
- Patent ductus arteriosus
Not used often due to it being VERY powerful
What are the side effects of indomethacin?
Severe gastric effects, thrombocytopenia, aplastic anemia, hyperkalemia (kidneys), coronary artery constriction
What is Celecoxib? Why would it be used?
A reversible COX-2 inhibitor
About as good as non-selective inhibitors, but might be used because of lower incidence of gastric irritation
When is misoprostol used? Why rarely used?
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)
What do all NSAIDs do to the kidneys?
Decrease renal blood flow, cause fluid retention, and may cause hypertension / renal failure
What are DMARDs used?
They suppress the proliferation and activity of lymphocytes and PMNs which reduce the inflammation, joint destruction, and slow the progression of rheumatoid arthritis
What is the first line drug for RA and what is it often used with?
Methrotrexate -> causes thymidine deficiency
Used in combination with Leflunomide (also reduces pyrimidine synthesis, but can cause serious liver disease)
What is the mechanism of action of leflunomide?
Reduction of pyrimidine synthesis by inhibition of dihydroorotate dehydrogenase
Why is hydroxychloroquine useful in rheumatoid arthritis?
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.
What particular patient populations is hydroxychloroquine useful in?
Useful in pregnant patients since methotrexate, leflunomide and cyclophosphamide are all teratogens
DO NOT USE in G-6-P DH Deficiency
When are TNF inhibitors used for RA?
In moderate to severe disease, since they are more effective than methotrexate in reducing symptoms
What are the three main TNF scavengers / inactivators? Main side effect?
- Etanercept
- Imflixima
- Adalimumab
Side effect is could cause TB if latent
How does etanercept work?
Enbrel - fusion protect which puts the human TNF receptor on the Fc fragment of IgG, works by scavenging TNF
How does abatacept work? When is it used?
Binds CD80 / CD86 on APCs to prevent T-cell activation via CD28
Used when anti-TNF agents are not working
How does Rituximab work? When is it used?
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
Can anti-TNF agents be used as a monotherapy, and what do you do if one doesn’t work?
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
