2 - NSAIDs, APAP, Eicosanoid Tissue Drugs

What is the MOA of aspirin?

irreversible inhibition of COX-1 & COX-2 → blocks conversion of arachidonic acid to PGG2/PGH2

What is the therapeutic use of aspirin?

anaglesia, antipyresis, anti-inflammatory action

• low dose: irreversible platelet TxA2 suppression for cardiovascular prophylaxis

What is the MOA of non-selective NSAIDs?

reversible, competitive inhibition of COX-1/COX-2

What is the therapeutic use of non-selecitve NSAIDs?

analgesia, antipyresis, anti-inflammatory action

What is the MOA of selective COX-2 inhibitors?

selective COX-2 inhibition, spares COX-1 dependent gastric PGE2 & platelet TxA2

What is the therapeutic use of selective COX-2 inhibitors?

anti-inflammatory/analgesic therapy with reduced GI toxicity (increased thrombotic risk from unopposed TxA2)

What is the MOA of misoprostol (PGE1 analogue)?

EP2/EP3 receptor agonist

What is the therapeutic use of misoprostol?

• prevention/treatment of NSAID-induced peptic ulcers (gastric cytoprotection)

• with mifepristone for medical termination of pregnancy

• cervical ripening/labor induction

What is the MOA of dinoprostone (PGE2)?

EP receptor agonist

What iis the therapeutic use of dinoprosone?

• cervical ripening & labor induction

• therapeutic termination of pregnancy

What is the MOA of carboprost tromethamine (15-methyl PGF2⍺)?

FP receptor agonist

What is the therapeutic use of carboprost tromethamine?

• postpartum hemorrhage refractory to oxytocin

• second-trimester therapeutic abortion

What is the MOA of alprostadil (PGE1)?

EP receptor agonist

What is the therapeutic use of alporstadil?

• maintains patency of the ductus arteriosis in neonates with ductal-dependent congenital heart disease

• erectile dysfunction

What is the MOA of epoprostenol (synthetic PGI2)?

IP receptor agonist

What is the therapeutic use of epoprostenol?

• pulmonary arterial hypertension

• continuous IV infusion, very short half-life

What isi the MOA of iloprost?

stable PGI2 analogue, IP receptor agonist

What is the therapeutic use of iloprost?

• pulmonary arterial hypertension (inhaled)

• peripheral vascular disease

What is the MOA of treprostinil?

stable PGI2 analogue, IP receptor agonist

What is the therapeutic use of trepostinil?

pulmonary arterial hypertension (SQ, IV, inhaled, oral)

What is the MOA of selexipag?

orally active, non-prostanoid selective IP receptor agonist

What is the therapeutic use of selexipag?

pulmonary arterial hypertension

What is the MOA of latanoprost, travoprost, tafluprost, bimatoprost?

• FP receptor agonists (prostaglandin analogues)

• increased uveoscleral outflow

What is the therapeutic use of latanoprost, travoprost, tafluprost, bimatoprost?

open-angle glaucoma/ocular hypertension

What is the MOA of latanoprostene bunod?

FP receptor agonist plus NO donor → increases both uveoscleral and trabecular-meshwork outflow

What is the therapeutic use of latanoprostene bunod?

open-angle glaucoma/ocular hypertension

What is the MOA of sildenafil, tadalafil, vardenafil, avanafil (PDE5 inhibitors)?

inhibits PDE-5, prolonging cGMP-mediated vasodilation

What is the therapeutic use of latanoprost, travoprost, tafluprost, bimatoprost?

erectile dysfunction; tadalafil also used for pulmonary arterial hypertension

What is the MOA of CysLT1-receptor antagonists (montelukast, zafirlukast)?

block cysLT1 receptor - antagonizes LTC4/LTD4/LTE4

What is the therapeutic use of CysLT1-receptor antagonists (montelukast, zafirlukast)?

asthma prophylaxis/maintenance; allergic rhinitis

What is the MOA of 5-lipoxygenase inhibitors (zileuton)?

inhibits 5-LOX - blocks synthesis of LTB4 and the cysteinyl leukotrienes

What is the therapeutic use of 5-lipoxygenase inhibitors (zileuton)?

asthma prophylaxis

What is the MOA of DP1-receptor antagonists (laropiprant)?

blocks the DP1-receptor - antagonizes PGD2

What is the therapeutic use of DP1-receptor antagonists (laropiprant)?

reduce niacin-induced flushing (PGD2-mediated cutaneous vasdilation

Where are NSAIDs distributed?

~50% concentration in synovial fluid

How are NSAIDs excreted and what is the resulting consideration?

hepatic first, then renally

• not recommended in hepatic/renal disease

What are therapeutic uses of NSAIDs?

• inflammation (musculoskeletal disorders)

• gout

• pain

• fever

• cardioprotection (only aspirin)

What are therapeutic uses of NSAIDs in musculoskeletal disorders?

• rheumatoid arthritis

• osteoarthritis

What are therapeutic uses of NSAIDs in pain?

• inflammatory pain of low-moderate intensity

• opioid alternative

• post-op

• menstrual

• bone pain (works better than opioids)

• headaches, migraines

What type of pain shows lack of efficacy of NSAIDs?

neuropathic pain

How are NSAIDs used in cardioprotection?

• aspirin reduces risk of serious vascular events & thrombotic stroke

• 81mg has lower GI ADE

What are ADE of NSAID therapy?

• GI

• cardiovascular

• blood pressure

• renal

• Reye’s syndrome (aspirin)

What are the GI ADE of NSAIDs?

• asymptomatic ulcers, erosions, or hemorrhage

• gastritis, hematemesis, ulcers, n/v

• most patients are. asymptomatic prior to diagnosis

What populations are high risk for GI ADE?

1. h. pylori infection

2. heavy drinkers

3. mucosal injury

4. concurrent use of GCC

Which NSAIDs are less prone to cause ulcers?

COX-2 rather than nonselective

What is the MOA of NSAID GI ADE?

inhibition of COX-1:

• inhibits PGE2, which inhibits acid secretion, enhances mucosal blood flow, promotes cytoprotective mucus → peptic ulcers

• inhibits TXA2 → may increase risk of GI bleed

Which NSAIDs cause cardiovascular ADE?

selective COX-2 inhibitors

What is the MOA of NSAID cardiovascular ADE?

• inhibits PGI2, which inhibits platelet aggregation and prothrombotic effect of TXA2

  • when TXA2 is unopposed → production of new platelets, increased platelet aggregation → heart attack/stroke

What is the BBW of NSAIDs?

• risk of heart attack or stroke with or without risk factors

• increased risk of HF

What are the effects of NSAIDs on blood pressure?

increases Na+ and water retention → hypertension

• more common with COX-2 selective

What. are the effects of NSAIDs on renal function?

PGE2 & PGI2 inhibition → vasoconstriction of afferent arteriole on each glomeruli, reducing normal kidney perfusion

What populations are at risk of renal ADE from NSAIDs?

• dehydrate

• hypervolemic

• congestive HF

• hepatic cirrhosis

• CKD

What is the role of NSAIDs in Reye’s syndrome?

aspirin and other salicylates

• avoid in anyone under 20yo with acute febrile illness

• acut encephalopathy, hepatomegaly, liver dysfunction, fatty infiltration of liver

What is the MOA of aspirin COX inhibition?

covalently acetylates subunits of COX-1 & -2 dimers

• irreversibly inhibits COX

• COX-1 inhibition of platelets lasts the lifetime of the platelet (8-12 days)

inhibits serine 529 in the COX hydrophobic channel, blocking AA from binding its catalytic site; prevents PG production and platelet activation

How long after stopping aspirin therapy may simple surgeries occur and why?

partial platelet pool recover (3 days) may be enough protection

Which acetic acid derivative is useful for treating patent ductus arteriosis?

indomethacin, successful closure of >70% of neonates

Define patent ductus arteriosus

the connection of the fetal pulmonary artery to the descending aorta does not close in utero due to prostaglandin-mediated dilation via PGE2 & PGE1

• failure to thrive is a common sign

• pulmonary htn & HF may develop if untreated

When is ketorolac used?

pontent analgesic but moderate anti-inflammatory drug

• PO & IM

• used for post-op pain

• max use of 5 days → high risk of renal dysfunction, steven-johnson syndrome, & gastric ulceration

What is the efficacy of diclofenac?

• very effective NSIAD

• almost as COX-2 selective as celecoxib

What are the therapeutic uses of propionic acid derivatives?

• rheumatoid arthritis

• juvenile arthritis

• osteoarthritis

What are off-the-box uses of propionic acid derivatives?

• pain

• gout

• headache

• tendonitis

• post op pain

• hangovers

What are the ADE of celecoxib?

• heart attack

• stroked

• GI upset/bleeding

• increased LFTs

• impaired renal blood flow

• nephrotoxicity

What is the contraindication of celecoxib?

coronary artery bypass graft surgery

What are the indications of celecoxib?

• osteoarthritis

• rheumatoid arthritis

• juvenile rheumatoid arthritis

• acute pain in adults

• dysmenorrhea

How does acetaminophen differ from NSAIDs?

APAP is an antipyretic and analgesic, but lacks anti-inflammatory activity

What is the effect of APAP at COX receptors?

weak, non-specific COX inhibitor, no anti-inflammatory effect

What are the warnings of APAP?

overdose: toxic metabolite, liver necrosis

What is the suggested MOA of APAP?

inhibits COX-3, which has high concentrations in the brain; may explain effectiveness for headache/fever

What is the toxicity of APAP?

• 10-15gm may cause hepatotoxicity

• >25gm as a onetime dose is potentially fatal

• increased risk for alcoholics >3 drinks daily

How is APAP toxic to the liver?

APAP is metabolized by CYP2E1 → N-acetyl-p-benzochinon imine (NAPQI), a toxic metabolite

• glutathione s-transferase metabolizes toxic metabolite into the inactive reduced form