Martin NSAIDS

Question 1

NSAIDS drug list

Answer 1

aspirin- prototype
ibuprofin
naroxen
ketoprofen
indomethacin
etodolac
ketorolac

Question 2

Selective COX-2 Inhibitors

Answer 2

Celecoxib

Question 3

Non-NSAID antipyretic/analgesic

Answer 3

Acetaminophen

a non-narcotic analgesic.

Question 4

Important Properties of NSAIDs

Answer 4

Analgesic = Pain Relief
Antipyretic = Anti-fever
Anti-inflammatory

Prototype Drug is ASPIRIN.

Question 5

NSAIDs: Common Mechanism of Action

Answer 5

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.

Question 6

Steroids vs COX-1/2 inhibitors

Answer 6

steroids inhibit phospholipases (disrupting formation of arachidonic acid)–> decreased prostaglandins AND leukotrienes AND lipoxins

COX 1/ 2 inhibitors inhibit cyclooxygenase –> decreased prostaglandins

Question 7

platelets and COX

Answer 7

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

Question 8

COX-1

Answer 8

expressed in most tissues.

* Constituitively active.

Question 9

COX-2

Answer 9

• 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

Question 10

Traditional NSAIDs non-selectively inhibit

Answer 10

both COX-1 and COX-2.

Question 11

COX Inhibition MOA

Answer 11

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.

Question 12

Selective COX-2 Inhibitors story

Answer 12

Celecoxib (valdecoxib, refocoxib have been withdrawn)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

Question 13

MI: Celebrex vs NSAID

Answer 13

Incidence increased by more with celecoxib than with NSAIDs, but both increase rates

Question 14

NSAIDs vs Aspirin

Answer 14

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!)

Question 15

prices

Answer 15

celcoxib pretty expensive

trade name much more expensive than generic aspirin

ibuprofen super cheap

Question 16

Analgesia

Answer 16

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.

Question 17

Antipyresis

Answer 17

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.

Question 18

Anti-Inflammatory Effects

Answer 18

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.

Question 19

Gastrointestinal Effects

Answer 19

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)

Question 20

Stomach Protective Factors

Answer 20

Pre-epithelial: mucus, bicarbonate, surface active phospholipids

Epithelial- cellular resistance, restitution, growth factors, prostaglandins, cell proliferation

Subepithelial- blood flow, leukocytes

Question 21

Gastrointestinal Side Effects of NSAIDS

Answer 21

Epigastric distress
Nausea
Vomiting
Microhemorrhage
Ulceration
Anemia

Question 22

NSAID Effects on Platelets and the Cardiovascular System

Answer 22

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)

Question 23

Low dose aspirin together with diet and exercise is useful for the prophylaxis of:

Answer 23

• coronary artery disease
• deep vein thrombosis
• unstable angina
• prophylaxis and treatment of MI and stroke

Question 24

Effects on the Kidney

Answer 24

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.

Question 25

Reye’s Syndrome

Answer 25

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.

Question 26

Therapeutic Uses: Analgesic-Antipyretics

Answer 26

Pain and Fever: symptomatic relief for pain of low-to-moderate intensity.

• Headache
• Dysmenorrhea
• Arthralgia
• Myalgia
• Neuralgia
• Arthritis

Question 27

Therapeutic Use as Anti-Inflammatory Agents

Answer 27

Rheumatoid Arthritis
Osteoarthritis
Gout and Crystal Arthritis
Systemic Lupus Erythematosus
Seronegative Spondyloarthropathy
Arthralgia
Myalgia
Bursitis, Tendonitis

Question 28

comparison of NSAIDs as anti-inflammatory agents

Answer 28

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.

Question 29

Dysmenorrhea

Answer 29

Prostaglandins released by the endometrium during menstration contribute to severe cramps and pain.
NSAIDs have proven very effective for treatment.

Question 30

Patent Ductus Arteriosus

Answer 30

PGE2 keeps ductus arteriosus open following birth.

* Indomethacin is the NSAID often used to stimulate closure of the patent ductus arteriosus.

Question 31

Familial Adenomatous Polyposis (FAP)

Answer 31

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

Question 32

aspirin and cancer

Answer 32

slightly decreased risk using aspirin

Question 33

aspirin kinetics- what happens if you exceed normal doses?

Answer 33

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)

Question 34

Adverse Effects

Answer 34

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

Question 35

Overt Toxicity

Answer 35

• 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

Question 36

Adverse Effects During Pregnancy

Answer 36

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

Question 37

Indomethacin and Related Drugs

Answer 37

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

Question 38

Ketorolac

Answer 38

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.

Question 39

Selective COX-2 Inhibitors- pros and cons

Answer 39

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

Question 40

Acetaminophen (Tylenol, etc.)

Answer 40

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

Question 41

acetominophen- when used

Answer 41

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