Martin NSAIDS Flashcards
NSAIDS drug list
aspirin- prototype ibuprofin naroxen ketoprofen indomethacin etodolac ketorolac
Selective COX-2 Inhibitors
Celecoxib
Non-NSAID antipyretic/analgesic
Acetaminophen
a non-narcotic analgesic.
Important Properties of NSAIDs
Analgesic = Pain Relief
Antipyretic = Anti-fever
Anti-inflammatory
Prototype Drug is ASPIRIN.
NSAIDs: Common Mechanism of Action
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.
Steroids vs COX-1/2 inhibitors
steroids inhibit phospholipases (disrupting formation of arachidonic acid)–> decreased prostaglandins AND leukotrienes AND lipoxins
COX 1/ 2 inhibitors inhibit cyclooxygenase –> decreased prostaglandins
platelets and COX
aspirin inhibits the COX enzyme covalently and you have to make new COX
platelets can’t make new COX and thus the baby aspirin has such a dramatic effect for MI; platelets forever affected by an aspirin molecule
COX-1
expressed in most tissues.
* Constituitively active.
COX-2
- Induced by cytokines and other inflammatory mediators.
This enzyme is the “real” target for anti-inflammatory effects
something that would only inhibit COX-2 would be a cleaner response
Traditional NSAIDs non-selectively inhibit
both COX-1 and COX-2.
COX Inhibition MOA
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.
Selective COX-2 Inhibitors story
Celecoxib (valdecoxib, refocoxib have been withdrawn)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
Contraindicated in aspirin allergy & 3rd trimester pregnancy
MI: Celebrex vs NSAID
Incidence increased by more with celecoxib than with NSAIDs, but both increase rates
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. (Indomethicin!)
prices
celcoxib pretty expensive
trade name much more expensive than generic aspirin
ibuprofen super cheap
Analgesia
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.
Efficacy of pain relief provided by NSAIDs is lower than opioids.
NSAIDs lack opioid effects of
- respiratory depression.
- development of physical tolerance/dependence.
Pain from integumental structures is relieved but not pain from hollow viscera.
Antipyresis
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.
Anti-Inflammatory Effects
PGE2 and PGI2 cause vasodilation are important mediators of localized * erythema and e* dema in inflammation. NSAIDs inhibit PG formation.
NSAIDs inhibit activation and function of inflammatory cells, may stabilize lysosomal membranes and inhibit phagocytosis.
Gastrointestinal Effects
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.
(*Histamine H2 receptor is a big player in production of acid in the stomach)
Stomach Protective Factors
Pre-epithelial: mucus, bicarbonate, surface active phospholipids
Epithelial- cellular resistance, restitution, growth factors, prostaglandins, cell proliferation
Subepithelial- blood flow, leukocytes
Gastrointestinal Side Effects of NSAIDS
Epigastric distress Nausea Vomiting Microhemorrhage Ulceration Anemia
NSAID Effects on Platelets and the Cardiovascular 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)
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
Effects 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.
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.
Therapeutic Uses: Analgesic-Antipyretics
Pain and Fever: symptomatic relief for pain of low-to-moderate intensity.
- Headache
- Dysmenorrhea
- Arthralgia
- Myalgia
- Neuralgia
- Arthritis
Therapeutic Use as Anti-Inflammatory Agents
Rheumatoid Arthritis Osteoarthritis Gout and Crystal Arthritis Systemic Lupus Erythematosus Seronegative Spondyloarthropathy Arthralgia Myalgia Bursitis, Tendonitis
comparison of NSAIDs as anti-inflammatory agents
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.
Dysmenorrhea
Prostaglandins released by the endometrium during menstration contribute to severe cramps and pain.
NSAIDs have proven very effective for treatment.
Patent Ductus Arteriosus
PGE2 keeps ductus arteriosus open following birth.
* Indomethacin is the NSAID often used to stimulate closure of the patent ductus arteriosus.
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
aspirin and cancer
slightly decreased risk using aspirin
aspirin kinetics- what happens if you exceed normal doses?
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 in saturates elimination mechanisms)
Adverse Effects
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
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.
Reye’s Syndrome
Drug-drug interactions
- antacids
- protein displacement; phenytoin, thyroxine, thiopental
- risk of bleeding for patients on anticoagulants
- uricosuric effect in gout patients
Overt Toxicity
- 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
Adverse Effects 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
Indomethacin and Related Drugs
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
Ketorolac
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.
Selective COX-2 Inhibitors- pros and cons
Celecoxib
Selective for COX-2.
Significantly less GI ulcers by endoscopy
No effect on platelets and bleeding time.
But caution with patients on warfarin.
Approved for osteoarthritis and RA.
Menstrual pain and acute post-operative pain
More expensive
Acetaminophen (Tylenol, etc.)
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
acetominophen- when used
Initial drug of choice for treatment of pain in osteoarthritis
* Combined with opioid agonists for additive postoperative pain relief
Acute Overdose: can be fatal due to delayed liver damage
