NSAIDs

My immunology background strikes again

Antipyretic, analgesic, anti-inflammatory

What are NSAIDs used for?

Nonselective reversible inhibitors of COX 1 and 2 (ASA is irreversible)

What is the MOA for NSAIDs

stimulus → Phospholipase A2 → free phospholipids → arachidonic acid → lipoxygenase (leukotrienes) or COX pathway (prostaglandins, TXA2)

Describe Eicosanoid synthesis

histamine

The release of leukotriene precursors (HpETE) is usually accompanied by the release of

Constitutive particularly in the stomach, inducible (2-4x), major product is TXA2 (platelet aggregation), inhibition by ASA reduces cardiac evens

Tell me about the COX-1 enzyme

Inducible (10-20x) by inflammatory response, found in the kidneys, lungs, macrophages (inflammatory cells), inhibited by NSAIDs and steroids

Tell me about the COX-2 enzyme

Increases lipocortin, decreasing PLA2 (both paths are blocked)

MOA for glucocorticoids

If we block the COX pathway, all the arachidonic acid is moved through the lipoxygenase pathway

What is the SHUNT hypothesis?

inhibit COX at low doses (200 mg), anti-inflammatory effect requires larger doses (600-800 mg)

Describe the dosage regimen for NSAIDs

blockage of the ATP binding site of IKK to prevent phosphorylation of IKB and activation of NFKB

Describe the anti-inflammatory MOA for NSAIDs (NOT TYLENOL)

Blocks the release of PGE2 (no increase of thermoregulatory set point)

Describe the Antipyresis MOA for NSAIDs

Only acts in the brain (no peripheral, no anti-inflammatory)

Why is acetaminophen the drug of choice for fever?

Decreases available PGs able to hit nocioreceptors (work peripherally)

Describe the analgesia MOA for NSAIDs

Decreases PGs (which normally potentiate contractions)

Describe the anti-parturition MOA for indomethacin → NO NSAIDS in PREGNANCY

Anti-inflammatory at 150-300 mg, ZERO ORDER KINETICS (enzymes become saturated at therapeutic range, large doses increase half-life), If you see tinnitus you took to much, DDI with NSAIDs (decreases anti-platelet effects)

Tell me about the acetylated salicylates (ASA)

little effect on platelets and thus risk for bleeding

Tell me about the non-acetylated salicylates

Choline salicylate, diflunisal, mag salicylate, salsalte, sodium salicylate, sodium thiosalicylate

Examples of non-acetylated salicylates

little anti-pyretic effect, not metabolized to salicylate

What is special about diflunisal

Diclofenac, etodolac, ibuprofen, indomethacin, meloxicam, nabumetone, naproxen, naproxen sodium , oxaprozin, piroxicam, keteorlac

Examples of NSAIDs

relatively COX-2 selective, less GI tox, some inhibition of the lipoxygenase, may increase MI risk

What is special about diclofenac?

COX-2 selective, less GI tox

What is special about etodolac?

some inhibition of the lipoxygenase, High incidence of CNS side effects in geriatric patients

What’s special about Indomethacin?

acutely moderate-severe pain ONLY, high risk of PUD

What is special about ketorolac?

Less risk of PUD, used for arthritis, dysmenorrhea, post-surgical pain, NO effect on platelets, Increase risk of MI or stroke

Tell me about the COX-2 inhibitors (Coxibs)

T1/2 of 10 hrs,

Quirks of Celecoxib

good bioavailability, low 1st pass, small Vd (highly bound), secreted via kidneys, concentration in synovial fluid is about 60%

NSAID pharmokinetics

ASA, diclofenac, etodolac, ibuprofen, indomethacin, ketorolac, salicylate

Short acting NSAIDs (under 6 hours) - underlined have slow release preparations available

diflunisal, naproxen, salsalte, sulindac, celecoxib

Intermediate acting NSAIDs (7-14 hours)

Nabumetone, oxaprozin, prioxicam, salicylate

Long acting NSAIDs (15+ hrs)

Peeps who have already had a stroke or MI, Coronary bypass, angina, High MI risk, DM + another risk factors

Who is a baby ASA recommended for?

ASA hypersensitivity, increased BP, nephrotoxicity, GI ulceration and bleeding; CNS reactions (rebound HA, dizziness)

ADRs of NSAIDs

Not true anaphylaxis but symptoms arise from increased LT synthesis (the SHUNT), associated with nasal poyps

What is special about ASA allergies?

rhinoconjunctivitis, angioedema, urticaria

Symptoms of ASA allergies - occurs within 3 hr

full expression of NE-led vasoconstriction (may interfere with anti-hypertensives)

MOA for HTN with NSAIDs

PGs help produce diuresis by increasing GFR so without that its not looking good especially for geriatric patients (can produce hyperkalemia, interstitial nephritis, and AKIs)

MOA for nephrotoxicity with NSAIDs

prior hx of PUD, prior NSAID intolerance, chronic EtOH usage, corticosteroid usage, chronic smoking, 60+

Who is at risk for GI ulcerations and bleeding with NSAIDs

Misoprostol + dicofenac (if not tolerated → celecoxib or NSAID + H2 or NSAID + PPI)

Treatment plan of NSAID associated GI ulceration

You use all your glutathione, so you get more NAPQI in the system (which is toxic)

Why can you kill yourself by taking a ton of tylenol? (NOTE: alcohol abuse increases risk)

gastric lavage + IV N.acetylcysteine

Treatment plan for tylenol OD

Allergies, autoimmune diseases, miminize transplant rejection

Indications for immunosuppressants

corticosteroids, calcineurin inhibitors, mTOR inhibitors, IMDH inhibitors, biologic, MABS

Classes of immunosuppressants

We need a signal transduction from CD3, followed by a signal transduction from Cd28, stimulation by IL-2. The TCR complex (includes CD3) (t-cell) binds to the MHC/peptide complex (APC) -> antigen recognition. B7 (APC) binds to CD28 (T-cell) -> signal transduction. IL-2 induces cell proliferation and eventual differentiation into an effector cell. 

How are T cells activated

Suppresses IL-2 production in T cells (no activation)

MOA for calcineurin inhibitors

cyclosporine, tacrolimus

Examples of calcineurin inhibitors

Prevents GVHD, T1/2 of 24 hours, 3A4 metabolism, swelling of gums

Tell me about cyclosporine

reduces risk of organ rejection, T1/2 is 11 hours, 3A4 and 3A5 metabolism

Tell me about Tacrolimus (Pro-graft)

suppresses intracellular signalling pathway important for cell growth and proliferation of T lymphocytes

MOA for mTOR inhibitors

Sirolimus, everolimus, temisirolimus

Examples of mTOR inhibitors

Prevents transplant rejection, coats coronary stents, 2-3 day T1/2, 3A4 metabolism

Tell me about sirolimus

Prevents transplant rejection, 30 hr T1/2, 3A4 and 3A5 metabolism, chemo agent for HER-2 neg breast cancer

Tell me about everolimus

Blocks DNA synthesis → no clonal expansion

MOA for IMDH inhibitors

Azathioprine, mycophenolate, lefunomide

Examples of IMDH inhibitors

Used for RA, Crohn’s, and transplants; T1/2 is 1.5 hr and 18 hrs,

Tell me about Azathioprine, mycophenolate ($$$)

Used for RA, T/12 is 2 weeks, hepatic metabolism, chemo agent for HER-2 neg breast cancer

Tell me about Lefunomide