pharmacology of non-opioid analgesics and NSAIDs

lecture given 3/17/2026

inflammation

a protective biological response to tissue injury or infection that aims to eliminate the cause of damage and begin tissue repair

what are the cardinal signs of inflammation?

redness (rubor)- increased blood flow

heat (calor)- vasodilation

swelling (tumor)- fluid leakage from vessel

pain (dolor)- activation of nociceptors

loss of function

what are the key chemical mediators of inflammation?

prostaglandins- pain, fever, vasodilation

leukotrienes- leukocyte recruitment

histamines- vasodilation, permeability

cytokines (TNFa, IL-1)- amplify inflammation

what are the drugs that act on eicosanoid pathways?

cox inhibitors- traditional nonselective inhibitors (NSAIDs) like asprin, ibuprofen, naproxen // cox-2 inhibitors like celecoxib // acetaminophen

glucocorticoids (upstream of cox)

arachidonic acid

fatty acid stored in cell membrane phospholipids

what is the pathway that produces AA, and what happens after AA is produced?

tissue injury or inflammation activates phospholipase A2 (PLA2)

PLA2 releases AA from the membrane

AA is converted into inflammatory mediators (eicosanoids) by two main enzyme pathways

+cyclooxygenase (cox) which produces prostaglandins, prostacyclin (PGI2), thromboxane (TXA2)

+lipoxygenase (lox) which produces leukotrienes

what are leukotrienes important for?

inflammation and leukocyte recruitment (important for asthma)

tldr what do NSAIDs do?

inhibit cox, decrease prostaglandins, decrease pain / inflammation / fever

what are the two sequential enzymatic reactions of cox?

cyclooxygenase activity- AA to PGG2

peroxidase activity- PGG2 to PGH2

PGH2 is the common precursor for several prostanoids like?

PGE2, PGD2, PGF2a, PGI2 (prostacyclin), TXA2 (thromboxane)

these molecules are lipid mediators involved in inflammation, pain, vascular tone, and platelet function

what are the functions of prostaglandins E2 (PGE2)?

major mediator of inflammation- fever (acts on hypothalamus), pain sensitization (nociceptor sensitization), vasodilation (redness and edema), gastric mucosal protection (decreased acid, increased mucous)

what are the functions of prostaglandins F2a (PGF2a)?

smooth muscle effects (uterine contraction)

thromboxane a2 (TXA2)

platelets, cox1

stimulates platelet aggregation, vasoconstriction, promotes thrombus formation

prostacyclin (PGI2)

endothelium, cox2

inhibits platelet aggregation, vasodilation, prevents thrombosis

cox1

constitiutive

physiological prostaglandins

gastric mucosal protection, platelet aggregation (TXA2), vascular homeostasis, kidney function

cox2

inducible

inflammatory prostaglandins

induced by cytokines, pain and inflammation, fever, increased in some cancers

traditional NSAIDs (aspirin, ibuprofen, naproxen)

nonselective- inhibit both cox1 and cox2 isozymes (to different degrees)

cox2 inhibition mediates antipyretic, analgesic, and anti-inflammatory actions

cox1 inhibition mediates many adverse effects

explain the anti-inflammatory therapeutic effect of NSAIDs

decreased inflammatory response by inhibiting cox2 at sites of inflammation

decreased prostaglandin synthesis leads to decreased vasodilation and edema

explain the analgesic therapeutic effect of NSAIDs

decreased pain by reducing prostaglandin mediated sensitization of nociceptors

peripheral and spinal mechanisms

explain the antipyretic therapeutic effect of NSAIDs

decrease fever by reducing PGE2 in the hypothalamus

promotes heat loss (vasodilation and sweating)

is the potency and emax of nonopioids higher or lower than opioids?

potency and emax are significantly higher on opioids

what are the major adverse effects of NSAIDs?

GI effects, CV effects, renal effects

explain the gastric toxicity of NSAIDs

decreased synthesis of cox1 derived gastroprotective prostaglandins in the stomach wall

risk increases with dose and duration

how can you manage NSAID GI toxicity?

avoid exceeding the recommended dose

add gastroprotective therapy-

+proton pump inhibitors- preferred option, omeprazole or esomeprazole

+prostaglandin analogue-restores gastric prostaglandins, often limited by adverse effects like diarrhea and cramping, mistoprostol

+fixed combinations like diclofenac + misoprostol or naproxen + esomeprazole

alternative strategies are to switch to acetaminophen or consider a cox2 selective NSAID (CV risk)

explain the CV risk with NSAIDs

increased bleeding time by inhibition of thromboxane (TXA) synthesis

NSAIDs inhibit cox1 in platelets, this reduces production of TXA2, inhibition of platelet aggregation and vasodilation leads to impaired platelet plug formation and prolonged bleeding time

relevant to dentistry because greater bleeding time during procedures, effect is strongest with aspirin

ADDITIONALLY

increased risk of thrombotic events like MI and stroke because of disruption of the balance between TXA2 and PGI2 (relative decreased in endothelial PGI2 leads to unopposed platelet aggregation and vasoconstriction)

risk increases with higher doses, longer duration of use, and preexisiting CV disease

explain the renal toxicity with NSAIDs

decreased renal prostaglandin synthesis- decreased afferent arteriolar vasodilation, decreased renal blood flow and GFR

fluid retention and decreased sodium excretion- leads to edema and hypertension

risk of acute kidney injury- especially in pts with compromised renal perfusion

occurs with both nonselective NSAIDs and cox2 selective inhibitors

can you use NSAIDs in pregnancy?

avoid near end of pregnancy- limit use after 20 weeks, avoid use after 30 weeks

can cause premature closure of the fetal ductus ateriosus, reduced fetal kidney function (low amniotic fluid), and possible prologation of labor

what is the preferred analgesic in pregnancy?

acetaminophen

what are the categories of NSAIDs?

proionic acid derivatives- ibuprofen, naproxen, ketoprofen

acetic acid derivatives- indomethacin, diclofenac, ketorolac

salicylates- aspirin, non-acetylated salicylates

ibuprofen (advil, motrin)

most commonly used NSAID in the US, shorter-acting tNSAID (1/2 life of ~2 hrs), dosing interval of 4-6 hrs, also formulated in combination with acetaminophen

naproxen (aleve, naprosyn)

longer acting tNSAID (1/2 life of ~14 hrs), dosing interval of 12 hrs, 10 more potent than aspirin, directly inhibits leukocyte function, less GI adverse effects than aspirin, may be the least cardiotoxic NSAID, has the most indications

how do acetic acid derivative NSAIDs work?

primarily inhibit cox which decreases prostaglandin synthesis, some have additional pharmacologic actions

indomethacin

potent anti-inflammatory NSAID, used in acute gout, higher incidence of adverse effects

diclofenac

potent analgesic and anti-inflammatory, widely used for musculoskeletal pain, associated with CV and renal risk

ketorolac

strong analgesic effect, available in IV and IM, used for short term treatment of moderate-severe pain, especially post surgery

shorter acting tNSAIDs

ibuprofen- 2hrs

indomethacin- 4-5hrs

longer acting tNSAIDs

naproxen- 12-17hrs

meloxicam- 20 hrs

what is the half life of cox2 selective NSAIDs (celecoxib)?

11hrs

what is the mechanism of action of aspirin?

the only NSAID that acetylates at the active site of cyclooxygenase and causes irreversible inhibition

what is the effect of low-dose aspirin (81mg/day) on platelets?

irreversible inhibition of platelet cox1

decreases TXA2 synthesis which leads to decreased platelet aggregation

platelet effect is permanent- cannot synthesize new cox enzyme, lasts the life of the platelet (4-7-10 days)

what is the clinical consequence of low dose aspirin?

prolonged bleeding time, basis for aspirin’s antiplatelet and cardioprotective effects

lower doses of aspirin (<100mg) selectively inhibit?

platelet cox1

higher doses of aspirin (>325mg) inhibit?

both cox1 and cox2, leading to inhibition of prostacyclin (PGI2) as well

an aspirin dosage of 81mg/day has what therapeutic effect?

antiplatelet

an aspirin dosage of 350-625mg every 24hrs has what therapeutic effect?

analgesia

an aspirin dosage of 3g/day has what therapeutic effect?

anti-inflammatory

increasing dose of aspirin has what effect?

decreasing platelet selectivity and increasing toxicity

what are the adverse effects that both aspirin and NSAIDs have?

increased bleeding time, GI toxicity, aspirin intolerance syndrom (AERD/Samter’s triad)

what adverse effects are unique to aspirin?

reye’s syndrome, hyperuricemia

aspirin intolerance (AERD)

mediated by leukotrienes (shunting of AA metabolism), more common in asthmatics

cross reactivity with nonselective NSAIDs

bronchospasams, rhinorrhea, and or/urticaria

cox2 selective inhibitors and low dose acetaminophen are usually tolerated

reye’s syndrome

acute encephalopathy, impaired liver function, fatty infiltration of the viscera (mitochondrial dysfunction)

aspirin and salicylates are not used for fever in children

acetaminophen is the preferred antipyretic/analgesic in children

what are the therapeutic uses of aspirin and salicylates?

topical applications- methyl salicylate is present in OTC transdermal patches for treatment of pain

CV uses- used prophylactically to decrease the risk of thromboembolic disorders like transient ischemic attacks and MI

t/f tNSAIDs interfere with antiplatelet activity of low dose aspirin

true- NSAIDs may block access of aspirin to its cox binding site

for a pt on the NSAID naproxen for osteoarthritis, what would you recommend to decrease the risk of ulcers and GI bleeding and maintain the therapeutic effect?

a) switch to aspirin

b) add cardioprotective dose of aspirin

c) add a proton pump inhibitor

d) switch to acetaminophen

c) add a proton pump inhibitor

among NSAIDs, aspirin is unique because it:

a) irreversibly inhibits cox

b) is associated with gastric disturbances

c) reduces fever

d) reduces the risk of colon cancer

e) selectively inhibits cox2

a) irreversibly inhibits cox

when does normal platelet function return after an analgesic dose of aspirin?

a) 8 hrs

b) 16 hrs

c) 24 hrs

d) 2 days

e) a week or more

e) a week or more

cox2 inhibitors

equal analgesic and anti-inflammatory efficacy as NSAID

lower GI effect risk (sparing of cox1 maintains synthesis of PG in gastric wall)

no effect on platelets (cox1)

CV toxicity (esp when used chronically)

renal toxicity

used in RA, osteoarthritis, ankylosing spondylitis

what is the only cox2 inhibitor currently on the market?

celecoxib

how do selective cox2 inhibitors work?

the active center of cox2 has a larger side pocket which can accommodate molecules with bulkier side chains than cox1

what are the therapeutic uses for cox2 inhibitor (celecoxib)?

juvenile RA, osteoarthritis, ankylosing spondylitis (require chronic administration)

not used for treating acute post-surgical dental pain

what are the adverse effects of cox2 inhibitor (celecoxib)?

GI toxicity- lower risk than naproxen and ibuprofen

renal toxicity- sodium retention and edema

CV toxicity

celecoxib has a higher risk of _____ events and a lower risk of ____ events,

while naproxen is the opposite, it has a higher risk of _____ events and a lower risk of ______ events

CV, GI

GI, CV

t/f a lot of the cox2 inhibitors introduced in the late 90’s and early 2000’s are still on the market

false- celecoxib is the only one still left but it has a boxed CV warning and explicit dose and duration limitation

rofecoxib was voluntarily withdrawn in 2004, valdecoxib was withdrawn in 2005, etoricoxib was never approved in the US

what was the post-withdrawl concensus of cox2 inhibitors?

CV risk was recognized as a class effect (not limited to one agent)

all non-aspirin NSAIDs carry CV risk boxed warning

clinical emphasis on lowest effective dose, shortest duration, patient CV risk stratification

why do cox2 inhibitors have a higher CV risk?

by removing PGI2 (prostacyclin) buffering while preserving platelet TXA2 (it functions unopposed)

decreased PGI2 induced vasodilation and inhibition of platelet aggregation also causes risks

what did the FDA rule on CV risk of NSAIDs in 2015?

FDA strengthened the exisiting label warning that non-aspirin NSAIDs increase the chance of heart attack or stroke

risk of MI or stroke can occur as early as the first weeks of using an NSAID but increased risk with longer use and higher doses

NSAIDs can increase risk of heart attack and stroke in pts with or without heart disease or risk factors for heart disease- depends on the drug and doses studied, pts with CV risk have a higher baseline risk

tldr NSAIDs

aspirin- high incidence of GI effects, useful anti-platelet action at low doses

ibuprofen and naproxen- OTC nonselective NSAIDs with moderate effectiveness

ibuprofen- most commonly used NSAID in US, also formulated in combo w opioids (oxycodone, hydrocodone) and acetaminophen

celecoxib- selective cox2 inhibitor, equal analgesic and anti-inflammatory efficacy, lower risk of GI effects

a CV risk warning is included on the label of ALL non-aspirin NSAIDs

acetaminophen

differs from tNSAIDs and cox2 selective NSAIDs in therapeutic effect and toxicity

antipyretic and analgesic activity

*no anti-inflammatory activity

no peripheral side effects

what is the mechanism of action of acetaminophen?

relatively weak cox inhibitory action compared with salicylates and NSAIDs

analgesic and antipyretic actions due to greater functional cox inhibition in the CNS than at peripheral sites

additional central mechanisms have been proposed (not really sure) like: serotonergic pathways, endocannabinoid signaling via acetaminophen metabolites, and cox3 (abandoned)

cox enzymes have 2 catalytic activities, which are?

cyclooxygenase site: AA → PGG2 (which tNSAIDs inhibit) and

peroxidase site: PGG2 → PGH2 (which acetaminophen primarily reduces activity at)

what happens at inflammatory tissues that makes acetaminophen not work?

high local peroxide concentratios

peroxides overcome acetaminophen’s inhibitory effect- cox activity continues and prostaglandin production persists

why does acetaminophen work in the CNS?

lower peroxide tone means acetaminophen is effective at analgesic and antipyretic effects

what kind of toxicity does acetaminophen have?

max dose of 3/4g/day, risk of fatality at 15g

hepatic toxicity- centrilobular hepatic necrosis (caused by a metabolite)

renal toxicity- uncommon at therapeutic doses, overdose may cause acute tubular necrosis

with chronic excessive use- rarely associated with renal papillary necrosis

rare acute interstitial nephritis

what metabolite of acetaminophen is toxic?

NAPQI- causes centrilobular hepatic necrosis

risk increased when CYP450 2E1 and 3A4 is induced and when glutathione is depleted

what is the antidote for acetaminophen, and how does it work?

n-acetylcysteine (NAC)

replenishes hepatic glutathione (GSH) which detoxifies the toxic metabolite NAPQI, it can also directly bind NAPQI

needs to be administered as soon as possible after overdose- most effective when given within 8 hrs

why is alcohol consumption with acetaminophen bad?

may increase the risk of APAP induced liver injury bc alcohol induces CYP2E1, increasing the conversion of APAP into NAPQI

chronic alcohol consumption can also inhibit CYP activity due to liver damage

GSH depleted in AUD

what are the therapeutic uses for acetaminophen?

mild to moderate pain, fever

since no anti-inflammatory activity, it is less effective than NSAIDs in some inflammatory conditions like RA

preferred antipyretic/analgesic for patients at increased risk of NSAID toxicity and children

what side effects does acetaminophen NOT have?

gastric toxicity, anti-platelet effect, inhibition of uric acid excretion, and allergy like symptoms in an aspirin intolerant individual

what should dentists know about therapeutic uses of acetaminophen for their pts?

max analgesic effect with 1g/4hrs

should not exceed 4g/day

often in combination with drug products containing an opioid analgesic such as codeine, hydrocodone, or oxycodone

not often in combination with ibuprofen

not useful as a preemptive analgesic

tldr acetaminophen

non-opioid, non-narcotic, analgesic and antipyretic agent

reversible inhibition of cox in CNS

used for post surgical dental pain, drug of choice for children with viral infections and pts intolerant to aspirin and other NSAIDs

DMARDs

disease modifying anti-rheumatic drugs

drugs that slow or hault progression of autoimmune joint disease

do not just relieve pain/inflammation, they modify the underlying immune process

when are DMARDs used?

in diseases like RA- immune system attacks synovium, cytokines drive inflammation, and chronic inflammation leads to cartilage and bone destruction

early therapy prevents irreversible joint damage and preserves function

what are the major categories of DMARDs?

convention synthetic immunomodulators (broad small molecules), extracellular biologic inhibitors (protein therapeutics, high MW), intracellular signal transduction inhibitors (targeted small molecules, low MW)

what drug is a convention synthetic immunomodulators (broad small molecules)?

methotrexate

what drugs are extracellular biologic inhibitors (protein therapeutics, high MW)?

cytokine neutralizers- TNFa inhibitors

t cell co-stimulation / surface modulators

cell depleting agents

what drugs are intracellular signal transduction inhibitors (targeted small molecules, low MW)?

calcineurin inhibitors, mTor inhibitors, JAK inhibitors

tldr DMARDs

immune modulators- act on different points of the inflammatory cascade

methotrexate at a low dose

anti-inflammatory

inhibits ALCAR transformylase- increases AICAR accumulation, increases adenosine (which activates A2A receptors on immune cells) leading to decreased t cell activation, decreased neutrophil function, and decreased cytokine production

methotrexate at a high dose

antineoplastic

inhibits DHFR- blocks DNA synthesis, cytotoxic to rapidly dividing cells

NOT anti-inflammatory

extracellular biologic inhibitors

large recombinant protein therapeutics that act outside the cell or at the cell surface to block immune signaling

core features- high MW, produced by recombinant DNA technology, highly target-specific, do NOT enter cells

cytokine neutralizers (TNFa, IL-6, IL-17, IL-12/13) are one category

they block inflammatory signal initiation at the extracellular level

TNFa

trimeri pro-inflammatory cytokine

binds TNFR1/TNFR2

activates NF-kB and MAPK pathways

acts upstream in the inflammatory cascade

amplifies IL-1, IL-6, cox2, adhesion molecules

how do TNFa inhibitors work?

monoclonal antibodies- bind soluble (± membrane) TNFa and prevent TNFR1/TNFR2 engagement

receptor fusion protein (etanercept)- soluble TNFR decoy (manufactured soluble TNF receptor)

net effect: decreased TNFa signaling, decreased NF-kB activation, decreased downstream cytokine amplification

how has the TNFa antagonists in the 2nd generation improved since 1st generation?

more humanized structures- less anti-drug antibody formation

improved molecular stability and longer half life- allows for longer dosing intervals

refined molecular design- more consistent therapeutic effect

what are examples of 2nd generation TNFa antagonists?

etanercept- receptor fusion concept

infliximab- chimeric antibody

adalimumab- fully human antibody

certolizumab- fab fragment and PEG (no Fc region)

what are the adverse effects/toxicity of DMARDs?

increased risk of infection, anti TNFa agents activate latent TB infection (pts need to be tested for TB status prior to use)

NSAIDs may increase risk of MI because…

a) inhibition of cox1 in platelets

b) inhibition fof TXA2 synthesis

c) inhibition of PGI2 synthesis in vascular endothelium

d) decreased vascular cox2 expression

c) inhibition of PGI2 synthesis in vascular endothelium

acetaminophen is safer in pts with…

a) asthma or aspirin intolerance syndrome

b) ulcers

c) bleeding disorders

d) viral illness (esp children)

e) all of the above

e) all of the above

a pt presents after an overdose of acteaminophen, risk of hepatotoxicity would be decreased by…

a) alcohol

b) CYP inducer

c) glutathione repleter

d) glutathione depleter

e) alkalinization of urine

c) glutathione repleter

which of the following drugs/classes of drugs does not have anti-inflammatory activity?

a) aspirin

b) antihistamine

c) acetaminophen

d) NSAIDs

e) TNFa antagonists

c) acetaminophen

which of the following pt characteristics is the most compelling reason for avoiding celecoxib in treatment of osteoarthritis?

a) history of AUD

b) history of diabetes

c) history of MI

d) history of osteoporosis

e) history of peptic ulcer disease

c) history of MI