Nonopioid Analgesics Flashcards
where do non-opioids work?
periphery
How do NSAIDs work?
nonsteroidal anti-inflammatory drugs
cyclooxygenase (COX) inhibitors
- Prevent binding of arachidonic acid to COX enzyme
- disruption of cell membrane –> arachidonic acid
- Arachidonic acid is processed by phospholipase 3 either by the COX or lipooxygenase pathway
If untreated
- Lipoxygenase –> asthma
- Cyclooxygenase –> prostaglandins –> pain causing
- Inhibit biosynthesis of prostaglandins
- Pain pathway
- Prevent other NT release
NOT targeting centrally. Looking at where the pain is happening. 1st order neuron!
Common analgesic, anti-inflammatory and antipyretic effects
cox enzymes
- COX -1 isoenzyme – nonselective
- COX -2 isoenzyme – selective
NSAIDs are either
non-selective
COX-2 selective (coxibs)
COX-1 isoenzyme
- Constitutively expressed (genes that are always “on”)
- Involved in numerous physiologic fns
- Maintenance of renal fn → impair renal fn
- Mucosal protection of the GI tract → if you block this, you’re more prone to developing ulcers
- Production of thromboxane A2 (plt aggregation) → if you block this you’re prone to bleeding!
- Von Willebrand’s factor – plts adhering to open area, plts release thromboxane A2, like AXE body spray of the body, and all the other plts come running
- Thromboxane a2 is released by plts to attract other plts
- Pts with CAD might be predisposed to heart attack
“take advil with food, make sure your kidneys work, drink a lot of water, you’re going to bruise easily” – all COX-1
ibuprofen, advil, naprocen
COX-2 isoenzyme
Expression induced by inflammatory mediators
Role in
-Mediation of pain, Inflammation, Fever
All the things we like
nonselective NSAIDs
- Limited use in the periop setting (GI toxicity and plt dysfn)
- Bone healing is delayed with NSAIDs
- Safe in the setting of primary bone healing (surgery was to fix the broken bone, works great)
Toradol (ketorolac) use, dosing, T1/2
most common non-selective NSAID used perioperatively
- Dose: 15 mg IV or IM q6h
- ↓ dosing in pts with renal fn (prob avoid it tbh) - ↓glomerular filtration, predisposes them to nephritis, but this is reversible in healthy pts
Now attacking pain at the scene of the crime. Now you have 2 ways to manage pain, if added to opioid.
-Not usually given preop, but we do give it at the end of some surgeries, but not good for bowel anastomosis surgeries (ketorolac ↓anastamosis healing and caused leakage). Once you get to clinical, just ask the surgeon if it’s ok to give.
T1/2 = 6 hrs
Celebrex (celecoxib)
is the only available COX-2 inhibitor for use
- Have less GI toxicity
- ↑ CV risk (not necessarily changing their plt aggregation, but bc you’re not blocking it you’re setting them up for CV injury)
- Commonly given as part of ERAS protocols
Dosing “COX-2, divide by 2”
- 400 mg PO preop
- 200 mg BID x 5d postop
PK of ALL NSAIDs
- All NSAIDs are weak acids (barbs, propofol, and NSAIDs)
- Low Vd (0.1-0.3 L/kg) (anything less than 42L is going to stay in the body water)
- Do we care about pKa of Celebrex? NO bc you don’t need it to cross the BBB.
- Plasma T1/2 is widely variable 30 minutes to hours. Drug specific
- GI absorption occurs rapidly
- ↑ protein binding – bind to albumin
- Liver metabolizes most NSAIDs
- Eliminated primarily by renal and biliary excretion
SEs of ALL NSAIDs
- Plt fn primarily through COX-1
- ASA noncompetitive NSAID (7-10 days for recycling) NOT THE CASE WITH THESE DRUGS
- GI complications range from mild ulcers to serious incidents such as perforation and bleeding – usually from chronic use. Risk factors include:
- Elderly
- Helicobacter pylori infection
- Hx of previous ulcer
- Concomitant use of ASA, anticoagulants or corticosteroids
- CV (more for COX-2)
- ↑ r/f myocardial infarction, CHF, and HTN
- In pts with CV risks, naproxen is NSAID of choice
- Less risk if nonselective COX
- Renal,Δs in renal fn include
- Sodium excretion, tubular fn, interstitial nephritis and reversible failure
- Risk factors:
- CHF, established renal dz, hx of DM, HTN, atherosclerosis & significant hypoalbuminemia
- Hypovolemia from any cause ↑s the potential of renal injury
- Liver
- Elevations in transaminase levels and liver failure have been reported
- Pulmonary
- Use of COX-2 in pts with hx of ASA-exacerbated dz
hypersensitivity and drug interactions
- *Hypersensitivity with NSAIDS rarely occurs. HOWEVER…
- Allergic rhinitis + nasal polyps + asthma = risk of anaphylaxis
Drug-drug interactions
- ↑bleeding with anti-plt agents*** or other anticoagulant (concomitant use is basically inhibiting plt fn in 2 different ways)
- ↓ digoxin and lithium clearance 2/2 prostaglandin inhibition and altered renal flow
ASA use
- Oldest and most widely used medicinal compound in the world
- Used to be a pain med, more now as antiplatelet
- Derivative of salicylic acid
- Rapidly metabolized
- Plasma esterases, erythrocytes and liver
2 main uses
- General analgesic
- “irreversible” plt inhibitor (7-10 days before return to normal, but not binding 100% of plts so you have some that can work. But the ones that are bound are so for 7-10 days).
- As opposed to advil, naproxen or Toradol, you’ll have plt inhibition for the half-life of that drug
ASA OD
-Toxicity related to drug acidity (NSAIDs are acids!) and prostaglandin inhibition
Sx’s
- N/V, abdominal pain, hearing impairment, CNS depression
- Higher doses: metabolic acidosis, renal failure, CNS changes (agitation, confusion, coma), and hyperventilation with respiratory alkalosis
- Urine alkalinization increases salicylate elimination (based on ionization)
- Give bicarb to alkalinize the urine
APAP use and PK
- Works close to the COX pathway? Might be a COX-3 pathway, but not sure at this time.
- Has analgesic and antipyretic properties
- Central analgesic effect through: Activation of serotonergic pathways (central NE and serotonin modulate pain! Activating serotonin pathways peripherally activates pain!). Antagonism of NMDA, substance P and NO pathways (periphery!)
- *No anti-inflammatory actions
PK
- Metabolized in the liver
- Leading cause of acute liver failure in US
- Chronic usage of <2g not associated with liver damage
-Damage to the liver result from metabolite:
N-acetyl-p-benzoquinoneimine leads to liver failure by depleting glutathione, a natural antioxidant
-Treatment aimed at removing acetaminophen (charcoal) and replacing glutathione (acetylcysteine administration) – mucomyst
