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
APAP dosing, PO and IV
Excellent PO bioavailability
- Dosing 325-650 mg q4-6h
- Total not to exceed 4,000 mg/24h (2,000 mg for chronic alcoholics)
An IV preparation (ofirmev) is available for clinical use
- 1000 mg IV q6hr
- Total not to exceed 4,000 mg/24h
- More expensive, would rather just tell pt to take 1-2 days preop
Gabapentin - use, PK
does not act on GABA receptors! Is a structural analogue of gamma-aminobutyric acid (GABA)
- Acts on voltage-dependent calcium channels inhibiting glutamate
- ↓ excitatory pathways
- Approved as an anticonvulsant med
- Has demonstrated some efficacy in neuropathic pain (*chronic pain)
Used as part of multimodal pain mgmt in ERAS protocols
- Generally accepted to be effective in reducing immediate postoperative pain and opioid consumption
- But causes respiratory depression
- Might have to take it for a few days preop and 2 wks after surgery
PK
- Absorption is limited to a relatively small part of the duodenum
- Absorption can be impaired by antacids
- Exhibit minimal protein binding (means it’s extremely ionized) and excreted without significant metabolism
Gabapentin dose, SEs
Dosing
- Preoperatively 1,200mg 1-2 h before surgery
- 600 mg Q 8 h x 14 days
- ERAS: gabapentin, APAP and celebrex
Side-Effects include:
-Sedation, dizziness or headache and visual disturbances
2019 lecture: “<1 day postop benefit of analgesia, 14 days of these SEs”
Lidocaine dosing
- 1.5 mg/kg bolus dose (IBW) induction
- 1-2 mg/kg/hr gtt
Lidocaine
is an amide local anesthetic
- Weak base
- pKa slightly above physiologic pH
Gtt’s are routinely used as part of a multimodal pain mgmt plan to supplement general anesthesia
-Mechanism of action not certain: may involve Na+ channels, Block priming of polymorphonuclear granulocytes (those granulocytes would have caused activation of pain receptors)
PK:
- Undergoes 1st-pass extraction in the lungs (4 so far! Which ones: propofol, fentanyl, sufentanil, lidocaine)
- Metabolized in the liver
- Metab prolonged in pts under general anesthesia
Not beneficial for all surgical procedures
- ↓ pain and speeds up return of bowel fn in lap cases
- ↓ pain, improves fn’l outcomes in prostatectomy, thoracic, and major spine cases
Accumulation is a concern; however, at doses given during ERAS protocols, serum levels are well below toxicity (liver dz)
- Normally they’ll tell you they have ringing in their ears, tongue tingly, “feel funny” – but in general anesthesia they can’t tell you those signs, so just draw a blood level
- Monitoring at-risk pts is advised
Magnesium Sulfate dosing
30-50 mg/kg bolus (2g bolus, don’t give them all at once, or do a 15-minute bolus)
10 mg/kg/h gtt (basically 1g/hr)
Magnesium sulfate
Analgesic properties related to
- Regulation of Ca++ influx into cells (↓ excitation/stimulation)
- Antagonism of NMDA receptors in CNS
- Antagonism of NMDA receptors + antagonizes Ca++
Dosing
- 30-50 mg/kg bolus (2g bolus, don’t give them all at once, or do a 15-minute bolus)
- 10 mg/kg/h gtt (basically 1g/hr)
- Studies show a ↓ in opioid consumption and pain
- SEs included bradycardia and hypotension
- Ca++ excitatory, Mg++ not so excitatory
Capsaicin
think of icy-hot
Transient receptor potential vanilloid (TRPV1) channel agonist
- Activation releases high-intensity impulses and releases substance P
- That receptor is activated by substance P
- Normally receptor stimulated –> releases substance P –> substance P stimulates the nerve ending –> nerve ending sends a signal
- What capsaicin does: TRPV1 receptor releases all the substance P it has no substance P left, can’t send a signal
- The major pungent ingredient of chili peppers and botanicals
- Applied topically for neuralgia and neuropathies (muscle aches and arthritis)
Available OTC in 0.025%, 0.075%, and 0.25% creams/transdermal patches
Ketamine dose
- 0.5-1 mg/kg prior to surgical incision
- MUCH LOWER DOSE, 0.5 mg/kg is common, followed by gtt
- Give right before surgical stimulation
Ketamine
NMDA antagonist modulates central sensitization
- Induced by incision and tissue damage
- Role in preventing opioid-induced hyperalgesia
Dosing
- 0.5-1 mg/kg prior to surgical incision
- MUCH LOWER DOSE, 0.5 mg/kg is common, followed by gtt
Give right before surgical stimulation
SEs
- Psychomimetic (remember to give midaz to decrease this!) Also remember that they will have nystagmus if you give enough.
- Dizziness, blurred vision, N/V
dexmedetomidine
Selective alpha2-agonist (locus ceruleus of brain)
- Blunts central sympathetic response
- Not so much as an analgesic, but a little more sedate. Use this as an adjunct.
Dosing
- 0.5-2 ug/kg
- 4 ug boluses!
Given at the beginning of the case, or at the end, but is NOT the sole analgesic!
SEs: Hypotension, Bradycardia
peripheral opioids
- Don’t usually have these, but if you have an injury your body can put some in the periphery
- Chronic pain pts do have some opioid receptors in the periphery
- Some surgeons will mix a little opioid into their local anesthetic and inject straight to surgical site, but it’s probably absorbed into the bloodstream?
- Analgesic effects are mediated by peripheral opioid receptors
- Peripherally acting opioids can reduce:
- Plasma extravasation, vasodilation, proinflammatory neuropeptides, immune mediators and tissue destruction
- Role in arthroplasty and inflammatory bowel dz
review of SC receptors
SC – substantia gelatinosa – rexed lamina 2 of dorsal horn
C fibers – rexed lamina 2 – substantia gelatinosa
C fibers – rexed lamina 5 – more A delta fibers???
