Mechanism of action of NSAIDS:

Inhibit cyclooxygenase (COX) activity to decrease the production of prostaglandins and thromboxanes

Two major isoforms are COX-1 and

   COX-2

Main COX Isoforms

 COX -1
   Constitutive - blood vessels, stomach,     kidneys, platelets

COX-2
   

Induced in inflammation and injury by
   cytokines and other mediators
   

Constitutive - brain, lung, GI tract,               kidneys

Pharmacologic Actions of NSAIDS 

1.  Analgesia

2.  Anti-inflammatory

3.  Anti-pyretic

4.  Anti-thrombotic

5.  Induce closure of ductus arteriosus

6.  Alleviate symptoms of dysmenorrhea

Most NSAIDs have similar efficacy

7.  Tocolytic activity (Indomethacin)

8.  Protect against colorectal neoplasia (Mechanism not understood)

9.  Retard progression of Alzheimer’s disease (Decrease plaque formation)

Gastrointestinal Side Effects of NSAIDS

1.  Gastrointestinal

  NSAIDS inhibit production of protective PGs

        resulting in ulcers, dyspepsia, diarrhea, etc

  - damage not prevented by H2 antagonists           or antacids

  - patient monitoring is essential

  - Misoprostol (PGE1 analog) prevents GI       damage

       NSAID + Misoprostol combinations available     

Renal Side Effects of NSAIDS

2.  Renal

  - NSAIDS inhibit production of PGs that    maintain renal blood flow

     resulting in nephritis and renal necrosis

  - NSAIDS can precipitate acute renal failure

     especially in compromised patients

Other Side Effects of NSAIDS

5.  Prolong gestation

6.  Precipitate bronchospasm

7.  CNS

  headache, dizziness

Pharmacokinetics of NSAIDS

Rapid, complete absorption

Highly protein bound

Mostly metabolized by CYP450 - hepatic

Renal excretion

Salicylates

  irreversibly inhibits COX-1 and COX-2

2.  Methyl salicylate

5.  Diflunisal

Salicylate Excretion Kinetics

1.  Primarily urinary excretion

         salicyluric acid, glucuronides,

         free salicylic acid

2.  Excretion kinetics

    i.  Dose-dependent

           a.  low dose aspirin

     first order kinetics

           b.   high dose aspirin

       saturation kinetics

3  Excretion kinetics, free salicylic acid

    ii.  pH-dependent

           a.  normal urine pH 5.4

      plasma pH 7.4, ratio = 100

                salicylate reabsorbed

          b.   at urine pH 8.4

       ratio = 0.1

                 salicylate excretion increased

Aspirin Pharmacology

1.  Alleviates mild to moderate pain

2.  Reduces fever

3.  Reduces inflammation - OA, RA

Prophylaxis of stroke, MI

Very low dose (75-100 mg/day)

Other Salicylates

1.  Methyl salicylate

   used only externally as counter-irritant

2.  Sodium salicylate

    less potent than aspirin

3.  Diflunisal

   not converted to salicylic acid in vivo

      weak anti-pyretic

     fewer antiplatelet and GI effects

      potent analgesic & antiinflammatory

      rare auditory side effects

Salicylate Side Effects

1.  Gastric bleeding/irritation

        ion-trapping effect

2.  Stimulate respiration

        directly and indirectly

3.  Change acid/base balance

  i.  respiratory alkalosis

      ii.  increased HCO3 excretion

      iii.  alkalosis compensated

 4.  Prolong bleeding time

5.  Reduce renal function

8.  CNS effects

stimulation followed by depression

nausea and vomiting

Contraindications with Salicylates

Acetic Acid Derivatives

Indomethacin

Sulindac

Etodolac

Femanates

Ketorolac

Tolmetin

Diclofenac

Indomethacin

1.  Indomethacin

  - reversible COX-1/COX-2 inhibitor

  - inactive metabolites

  - high incidence of side effects

  - interactions with furosimide,

  b-blockers, ACE inhibitors

  - uses:  tocolytic agent

   closure of ductus arteriosus

   arthritis

   acute gout  

Sulindac and Etodolac

2.  Sulindac

- less potent than indomethacin

- pro-drug - active sulfide metabolite

- useful in RA, OA, AS, acute gout

3.  Etodolac

- somewhat selective COX-2 inhibitor

- low GI toxicity

- useful in RA and OA, post-op pain

Femanates

4.  Femanates

Ketorolac and Tolmetin

5.  Ketorolac

  - short-term treatment ONLY - 5 days

  - used for post-op pain (i.v., i.m. , p.o.)

  and in ocular solution

  - contraindicated in:  labor

    renal impairment, bleeding disorders

    NSAID sensitivity, GI disorders

  - good analgesic, poor antiinflammatory

  - useful in OA, RA, persists in synovium

  - high incidence of GI side effects

Diclofenac

7.  Diclofenac

  - selective for COX-2

  - useful in RA, OA, AS, acute pain,       dysmenorrhea

  - useful in eye - post-op

Propionic Acid Derivatives (General)

Non-selective COX inhibition

Usually better tolerated than aspirin

  and indomethacin

Generally do not alter effects of oral hypoglycemic drugs or warfarin

Used in RA, OA, dysmenorrhea, fever, mild to moderate pain, tendonitis, bursitis, migraine

Drug interactions similar to other NSAIDS

Types of Propionic Acid Derivatives 

  1.  Ibuprofen - half-life 2-4 hr

  2.  Naproxen - half-life 14 hr

  3.  Ketoprofen - half-life 2 hr

  not recommended for acute use due to

   extended release from metabolite

   4.  Oxaprozin - half-life 40-60 hr

  5.  Flurbiprofen - half-life 6 hr, useful in eye

Enolic Acid Derivatives 

1.  Piroxicam

  inhibits COX-1>>COX-2

  long plasma half-life (45-50 hr)

  useful in OA, RA, acute gout

  many side effects

  drug interactions:  aspirin, warfarin

2.  Meloxicam

  inhibits COX-2>COX-1

  useful in OA

3.  Nabumatone

  - pro-drug - active metabolite

  - non-selective COX inhibitor

  - useful in OA, RA

  - low incidence of side effects

Coxibs (General)

Selective COX-2 inhibition

Fewer GI side effects

Few effects on platelet function

May precipitate CV events

Renal toxicity same as other NSAIDS

Not first-choice drugs - costly

Used for OA, RA

Coxibs Examples

1.  Celecoxib – least selective

    - metabolized by CYP2C9

     - inhibits CYP2D6

     - less CV risk

2.  Rofecoxib, Valdecoxib,

     removed from market, 2004-2005

3.   Second Generation

    Etoricoxib, Parecoxib

Acetaminophen General (APAP)

Widely used analgesic, antipyretic

Analgesic efficacy equivalent to aspirin

Antipyretic effect likely due to COX inhibition in brain

Weak antiinflammatory, antiplatelet and GI effects

Acetaminophen Analgesia

Potential mechanisms of analgesic action:

via parent compound

may be indirect

Potential mechanisms of analgesic action:

via active metabolite (AM404) formed in brain 

  a.  AM 404 is an endogenous fatty acid amide that inhibits reuptake of anandamide (cannabinoid)

  b.  agonist at TRPV1 (vanilloid) receptors

Acetaminophen Toxicity

Most common cause of liver failure in USA

Responsible for more ER visits than any other drug

140,000 poisonings in 2006, >100 deaths

Many are unintentional

  many products contain APAP

   max daily dose difficult to calculate

  toxicity can occur at therapeutic doses

Acetaminophen Toxicity Specifics

Specific toxicity - hepatic necrosis

  from toxic metabolite (NAPQ1)

  1. depletes hepatic glutathione

  2. causes necrotic cell death

Antidote is N-acetylcysteine (NAC)

Early diagnosis essential for NAC treatment

  within 8-10 hr; after 10 hr decreased     effectiveness

Toxic risk best predicted by dose and time

Toxicity Symptoms of Tylenol 

1.0.5-24 hr - pallor, lethargy, nausea, vomiting, diaphoresis, malaise

Drug Interactions with Tylenol

Drugs that are metabolized by CYP450 enzymes

  - anticonvulsants (barbiturates, etc)

Vit K antagonists - warfarin

Ethanol increases risk of hepatic toxicity

St. John’s wort