2-23 NSAIDs Flashcards
What is the NSAIDs drug list? Prototype?
Aspirin [generic] - prototype
Ibuprofen [ADVIL, MOTRIN, NUPRIN]
Naproxen [ALEVE, NAPROSYN]
Ketoprofen [ORUDIS]
Indomethacin [INDOCIN]
Etodolac [LODINE]
Ketorolac [TORADOL] (IV, IM)
What are the selective COX2 inhib drugs? Non-NSAID antipyretic/analgesic?
¡Selective COX-2 Inhibitors
lCelecoxib [Celebrex]
¡Non-NSAID antipyretic/analgesic
lAcetaminophen [TYLENOL]
la non-narcotic analgesic.
What are the important properties of NSAIDs?
¡Analgesic = Pain Relief
¡Antipyretic = Anti-fever
¡Anti-inflammatory
Prototype Drug is ASPIRIN
What are the common mechanisms of action for NSAIDs?
All NSAIDS inhibit the enzyme cyclooxygenase (COX).
Cyclooxygenase is a key enzyme responsible for the synthesis of prostaglandins.
Prostaglandins contribute to a number of inflammatory processes.
Common mechanism of action leads to common side effects.
What do COX inhibitors target? Steroids?
adg
Why are COX inhibitors and steroids so effective at dealing with pain in different places?
Stops precursors that make tissue-specific isomerases
What are some prostaglandin receptors?
All GPCRs that make intracellular signals
How does aspirin work?
When ASA binds serine, and will covalently bind and inactivate enzymes
- ASA leaves behind a permanent residue on enzyme
- all other COX inhib do reversible binding to active spot
What’s the difference between COX1 and COX2
COX-1
expressed in most tissues.
Constituitively active, regulated by amt of substrate arachadonic acid
COX-2
Induced by cytokines and other inflammatory mediators. - only shows with inflammation
This enzyme is the “real” target for anti-inflammatory effects
COX-3 – brain, role(?) splice variant of COX-1
Traditional NSAIDs non-selectively inhibit both COX-1 and COX-2.
What is the MOA for COX inhibitors?
Mechanism of Action:
aspirin covalently (irreversibly) inhibits COX 1&2
recovery of COX in most tissues is by synthesis of new enzyme.
Platelets cannot synthesize new COX, so inhibition is irreversible.
other NSAIDs produce reversible inhibition of COX.
What are the selective COX-2 inhibitors?
¡Celecoxib [Celebrex]
¡Valdecoxib [Bextra] Withdrawn
¡Refocoxib [Vioxx] Withdrawn
What is the specificity, effects, clinical indications and contraindications for COX2 inhib.?
Celecoxib [Celebrex]
Valdecoxib [Bextra] Withdrawn
Refocoxib [Vioxx] Withdrawn
Selective for COX-2 (300-400X)
Significantly less GI ulcers [by endoscopy].
Do not effect platelets and bleeding time.
Originally approved for dysmenorrhea, osteoarthritis, and rheumatoid arthritis, acute post-operative pain
lContraindicated in aspirin allergy & 3rd trimester pregnancy
Why were so many COX2 inhib taken off the market?
slightly increased risk of MI, but not clear cut what caused MI
What are the advantages & disadvantages of NSAIDs vs aspirin?
Advantages: some NSAIDs are marginally superior to aspirin because they:
are more potent
are more efficacious at tolerated doses.
cause less gastrointestinal irritation or other side effects
have longer duration of action so taken less frequently (qd or bid)
Disadvantages
Newer NSAIDs are more expensive than aspirin
Some are more toxic than aspirin.
What is the relative cost of NSAIDs?
For standard treatment (1 month) of rheumatoid arthritis:
Enteric coated aspirin (generic) $18.00
Enteric coated aspirin (Ecotrin) $50.40
Ibuprofen (generic) $2.30
Ketoprofen (Orudis) $138.00
Diclofenac (generic) $46.20
Celecoxib (Celebrex) $84.00
How are analgesics effective in relieving pain, other than blocking prostaglandin synthesis?
PGE2 sensitizes pain nerve endings to the action of bradykinin, histamine, and substance P. Aspirin blocks PGE2 formation.
NSAIDs are mild analgesics effective against pain of low-to-moderate intensity.
NSAIDs can be superior to opioids for relief of some forms of post-operative pain and pain associated with inflammation.
How do NSAIDs compare to opioids? Effectiveness at relieving pain, side effects, etc.?
Efficacy of pain relief provided by NSAIDs is lower than opioids - more mild analgesic effects, but good at alleviating pain in hollow organs.
NSAIDs lack opioid effects of
respiratory depression.
development of physical tolerance/dependence.
Pain from integumental structures is relieved but not pain from hollow viscera.
Other than the analgesic effect, what else are COX inhib effective at relieving?
Antipyretics
Temperature control center in hypothalamus regulates body temperature.
Pyrogens (cytokines) from lymphocytes lead to higher temperature set point, i.e., fever.
Heat generation (metabolism) increases and heat loss (vasodilation) decreases.
NSAIDs that can cross BBB effectively suppress this response.
In addition to the antipyretic and analgesic effects, what other effect of COX inhib is helpful?
PGE2 and PGI2 cause vasodilation are important mediators of localized erythema and edema in inflammation. NSAIDs inhibit PG formation.
NSAIDs inhibit activation and function of inflammatory cells, may stabilize lysosomal membranes and inhibit phagocytosis.
What are the GI effects of NSAIDs?
PGI2 inhibits gastric acid secretion.
PGE2 and PGF2a stimulate synthesis of bicarbonate and mucus.
PGE2 promotes mucosal blood flow.
NSAIDs inhibit all of these effects which leads to GI irritation.
What is the effect of NSAIDs on the stomach?
Fatty acids can convert into prostaglandin
- this process is blocked by NSAIDs
prostaglandins are then used to downregulate the H+/K+ ATPase pump in parietal cells, leading to decreased acid secretion
prostaglandins upregulate mucous, bicarb production in superficial epithelial state
prostaglandins improve blood flow to the stomach
What are the GI ADRs of NSAIDs?
Epigastric distress
Nausea
Vomiting
Microhemorrhage
Ulceration
Anemia
What the effects of NSAIDs on platelets and the CV system?
Platelets have thromboxane synthetase and make TXA2, a potent vasoconstrictor and activator of platelet aggregation and release.
Endothelial cells make PGI2 (prostacyclin) an inhibitor of platelet aggregation and a vasodilator.
Low doses of aspirin irreversibly inhibit COX and platelet aggregation for the life of the platelet (8-11 days)
What is ASA, in addition to lifestyle changes, useful in prophylaxis of?
Low dose aspirin together with diet and exercise is useful for the prophylaxis of:
coronary artery disease
deep vein thrombosis
unstable angina
prophylaxis and treatment of MI and stroke
What are the effects of COX inhibitors on the kidney?
Little effect in normal subjects.
PGs oppose effect of vasoconstrictors.
In situations where there are high levels of circulating vasoconstrictors, e.g., compensated congestive heart failure, chronic renal disease, NSAIDs can reduce renal blood flow.
Retention of sodium and water. Reduced effectiveness of hypertensive regimens.
NSAIDs and COX-2s should be used with caution in patients with reduced renal function, heart failure, liver dysfunction, or in patients on ACE inhibitors or diuretics, especially elderly patients
What are the disease states leading to increased vasoconstrictors? What is the response of renal blood flow?
What is Reye’s syndrome?
Reye’s syndrome is a rare but often fatal consequence of infection with chicken pox, varicella and influenza viruses. Liver damage and encephalopathy.
Use of aspirin and salicylates are associated with the development of Reye’s syndrome. The use of salicylates in children or adolescents with chicken pox or influenza is contraindicated!
What sorts of mild problems are NSAIDs ideal for?
Therapeutic uses: Analgesic-Antipyretics
Pain and Fever: symptomatic relief for pain of low-to-moderate intensity.
Headache
Dysmenorrhea
Arthralgia
Myalgia
Neuralgia
Arthritis
What are some therapeutic uses for anti-inflammatory agents/NSAIDs?
Rheumatoid Arthritis
Osteoarthritis
Gout and Crystal Arthritis
Systemic Lupus Erythematosus
Seronegative Spondyloarthropathy
Arthralgia
Myalgia
Bursitis, Tendonitis
As anti-inflammatory agents, which NSAIDs are used and for how long? What are the benefits and limitations?
¡NSAIDs other than aspirin are typically used for chronic treatment, e.g., ibuprofen or naproxen.
¡COX-2 specific NSAIDs were preferred for chronic treatment, but there use now (Celebrex) is still controversial.
¡Lesser incidence and less serious GI side effects was the proposed benefit of Celebrex.
¡NSAIDs suppress the clinical signs in rheumatic disease, but subsequent tissue damage is not halted.
¡NSAIDs do not induce remission.
Why should you give Tylenol as an antipyretic to kids with fever?
Because HSV viruses, influenza, and Reye’s syndrome are all bags of dicks.
Why are NSAIDs so effective for dysmenorrhea?
¡Prostaglandins released by the endometrium during menstration contribute to severe cramps and pain.
A kid is born with a PDA. What do you do?
PGE2 keeps ductus arteriosus open following birth.
Indomethacin is the NSAID often used to stimulate closure of the patent ductus arteriosus.
Why are NSAIDs useful in familial adenomatous polyposis (FAP)?
Studies show reduction in number of polyps with COX-2 inhibitors
COX-2 is overexpressed in several human cancers
Increasing evidence suggest that COX-2 inhibitors, and perhaps NSAIDs in general, may be effective for prevention or treatment of certain cancers, especially for colorectal cancer
What is the evidence that ASA prevents cancer?
reduces overall cancer risk, <1 case/1000 for low risk up to <12 case/1000 for high risk populations
What are the kinetics of ASA?
Aspirin displays zero-order elimination kinetics at high doses.
The plateau principle does not apply under these conditions and plasma drug levels increase disproportionately to dose.
Too much aspirin = tinnitus, time to stop
What are the ADRs of ASA?
Gastrointestinal irritation
epigastric distress, nausea, vomiting, microscopic bleeding, ulceration, anemia
Prolonged bleeding time
(anti-platelet effect)
Patients scheduled for surgery taken off of aspirin for one week prior
What is the relationship between hypersensitivity and ASA?
Hypersensitivity
asthma, nasal polyps, chronic urticaria predisposed
progresses from hives, nasal secretion and edema to acute asthma attack, severe dyspnea, hypotension, and shock
Hypersensitivity to aspirin is a contraindication to therapy with any NSAID.
(D/t possible overproduction of leukotrienes, triggering asthma)
- cross reaction with any NSAID too
What are the drug-drug interactions of ASA?
¡Drug-drug interactions
lantacids
lprotein displacement; phenytoin, thyroxine, thiopental
lrisk of bleeding for patients on anticoagulants
luricosuric effect in gout patients
What does overt toxicity of ASA cause?
Salicylism - mild intoxication
nausea, vomiting, tinnitus, hyperventilation, headache, mental confusion, dizziness
Overdose = acute medical emergency
fever, dehydration, delirium, hallucination, convulsions, coma, respiratory and metabolic acidosis, death
children especially vulnerable
What are the ADRs of ASA during pregnancy?
Avoid use during third trimester unless absolutely necessary
low birth weight
increased perinatal mortality
anemia
antepartum and postpartum hemorrhage
prolonged gestation
premature closure of ductus arteriosus
What are the uses and limitations of indomethacin?
Indomethacin is more potent than aspirin
Very efficacious anti-inflammatory agent
Toxicity (worse than aspirin) limits its usefulness
Not used for routine analgesia
Can be used in resistant rheumatoid disease
Suppression of uterine contraction in preterm labor and closure of patent ductus arteriosus
What are the uses of ketorolac (Toradol)?
Potent analgesic
Weak antiinflammatory effect
Can be used orally, IM, or IV
Used for post-operative pain, as an alternative to opioids (not obstetrics)
Unlike opioids, it is not associated with tolerance, withdrawal effects, or respiratory depression.
What are the uses and limitations of selective COX-2 inhib?
¡Celecoxib [Celebrex]
¡Selective for COX-2.
¡Significantly less GI ulcers by endoscopy
¡No effect on platelets and bleeding time.
lBut caution with patients on warfarin.
¡Approved for osteoarthritis and RA.
¡Menstrual pain and acute post-operative pain
¡More expensive
What are the uses and limitations of Tylenol?
¡Non-narcotic Analgesic
¡Antipyretic
¡Very weak anti-inflammartory activity
¡Not an NSAID, not effective for inflammation
¡Well tolerated, lacks GI and platelet side effects
¡Useful analgesic, antipyretic for children and those with contraindications to aspirin
When is Tylenol frequently used? What does an overdose cause?
¡Initial drug of choice for treatment of pain in osteoarthritis
¡Combined with opioid agonists for additive postoperative pain relief [Percocet, Lortab, Vicodin, Darvocet, Tylenol with Codeine]
¡ Acute Overdose: can be fatal due to delayed liver damage
