PCOL M3L3

INFLAMMATION

• A non-specific immune response against an adverse stimulus.

  1. Microbial invasion

  2. Physical Injury

INFLAMMATION

Purpose: For protection and a part of healing process

Calor

Heat

Rubor

Redness

Swelling

Tumor

Dolor

Pain

Functio laesa

Loss of Function

NSAIDs, Glucocorticoids

Relief of symptoms and the maintenance of function

DMARD’s

• Slowing or arrest of the tissue-damaging process

Weak cox inhibitor

• 1st line agent for pain in OA

ACETAMINOPHEN

• Weak cox inhibitor in the periphery:

  • Analgesic effect: Weak cox inhibitor - 1st line agent for pain in OA

  • Antipyretic: High antipyretic effect than analgesic

  • Anti Inflammatory: No inflammatory effect

ACETAMINOPHEN

• Advantages:

  • vs. Aspirin: No hyperuricemia

  • Safe in pregnancy, lactation, children

ACETAMINOPHEN

• Major risk: hepatotoxicity —> NAPQI (N-acetyl-p-benzoquinone imine)

N-acetyl-p-benzoquinone imine

NAPQI

ACETAMINOPHEN

• Risk factors for APAP induced hepatotoxicity

  • > 4g/day (8 tabs per day)

  • Pre-existing liver disease

  • Concomitant use of CYP1A2 inducers

Nabumetone

All are weak organic acids except

Nabumetone

 non-acidic, only prodrug NSAID

NSAIDs

MOA: block COX enzyme = inhibit PG synthesis

NSAIDs

• Majority of the side effects are due to the blockade of COX1 by nonselective NSAIDs

COX1

Constitutive enzyme/homeostatic enzyme

COX1

Produce PGs for maintenance function (homeostasis)

COX1

• Cytoprotection 

COX1

• Renal vasodilation = enhance diuresis

COX2

• Responsible for pain & inflammation

COX2

• Inducible

COX2

Formation is due to adverse stimuli

COX2

Produce PG needed for pain of inflammation

Aspirin

Irreversible non-selecive cox inhibitor

Tolmetin, Indomethacin,Sulindac, Piroxicam

Relatively COX-1 Selective

Ibuprofen, Paracetamol

Less COX-1 Selective

Naproxen, Diclofenac, Flurbiprofen, Nabumetone

Equipotent COX-1 And COX-2

Nimesulide, Celecoxib, Rofecoxib

Selective COX-2 inhibitors

Meloxicam

Preferentially selective COX-2 inhibitor

ASPIRIN AND SALICYLATES

Prototype, the only irreversible COX inhibitor

Anti-platelet

Low dose aspirin

Anti-inflammation, analgesic

High dose aspirin

Aspirin toxicology (with other NSAID)

• GI effects

  • Gastritis and GI ulcer bleeding

  • Common in nonselective COX inhibitor

Misoprostol

1st kine agent for aspirin toxicity

Reversible decrease in GFR

• Associated with any NSAID = nephrotoxicity (if long term & can damage the kidney & associated with the blockade of COX1

• PG is good for kidneys - causes renal vasodilation = Increase GFR = Diuresis

• Inhibit COX = inhibit PG = renal vasoconstriction = reduce GFR

NSAID induced bronchial asthma

• COX is inhibited = more arachidonic acid is converted to LT = increase SRSA = bronchoconstriction (contraindicated in asthma, leukotrienes)

Zileuton

5-lox inhibitor

-lukast (Montelukast, Zafirlukast)

LTD4 antagonist, directly targets leukotrienes

Hyperuricemia

•  C/I (contraindication) to gout

Hyperuricemia

• Ex. ASA (aspirin), Tolmetin, Salicylates — C/I to gout

Reye’s syndrome

ASA + Child with viral syndrome

Reye’s syndrome

Fatal: Hepatic failure, encephalopathy

PYRAZOLONE DERIVATIVES

-one

PYRAZOLONE DERIVATIVES

• Ex. Phenylbutazone, Dipyrone, Sulfinpyrazone

Sulfinpyrazone

• not and NSAID, uricosuric (excretion of uric acid)  instead

PYRAZOLONE DERIVATIVES

Powerful analgesic and anti-inflammatory

PYRAZOLONE DERIVATIVES

• Withdrawn from the market — toxic

Hematotoxicity

Agranulocytosis ( WBC) = prone to infection

Hematotoxicity

Thrombocytopenia = low platelets = prone to bleeding — Aplastic anemia = reduce RBC, WBC, Platelet

Nephrotoxicity

Acute tubular necrosis

Nephrotoxicity

Anasarca - massive edema

Nephrotoxicity

Nephrotic syndrome - massive albuminuria

Anasarca

•  massive edema

Nephrotic syndrome

•  massive albuminuria

INDOLE DERIVATIVES

Blocks COX1 >> COX2

INDOLE DERIVATIVES

Ex. Indomethacin

INDOLE DERIVATIVES

Tx pain in acute gout

INDOLE DERIVATIVES

Mgt of Bartter’s syndrome (impaired salt reabsorption)

Indomethacin

Mgt of Patent Ductus Arteriosus

Ductus arteriosus

found in blood vessels of fetus connecting aorta and pulmonary artery

Ductus arteriosus

open ductus arteriosus lead to mixed up of oxygenated and deoxygenated blood leading to impaired oxygenation

Ductus arteriosus

PG is responsible for opening of ductus arteriosus

Ductus arteriosus

COX inhibition = less PG = closure of ductus arteriosus

IBUPROFEN, NAPROXEN

Analgesic + anti-inflammatory + antipyretic

IBUPROFEN

Safest NSAID in children

NAPROXEN

Fever of malignancy (Fever of unknown origin/reason)

KETOPROFEN, FLURBIPROFEN

Analgesic + anti-inflammatory

Sulindac

sulfonamide like compound

TRUE PHENYLACETATES

• Sulindac - sulfonamide like compound

• Alclofenac

• Diclofenac

Ketorolac

 treatment of acute pain postoperative

Nabumetone

•  only prodrug, only non-acidic NSAID

Nabumetone

Active metabolite: 6-Methoxy-2-naphthylacetic acid

ACETIC ACID DERIVATIVES

• Ketorolac - treatment of acute pain postoperative

• Etodolac

• Nabumetone – only prodrug, only non-acidic NSAID

• Active metabolite: 6-Methoxy-2-naphthylacetic acid

FENAMATES

Mefenamic acid, Meclofenamic acid, Flufenamic acid

FENAMATES

• Analgesic only

FENAMATES

• Never given in children

OXICAM DERIVATIVES

-oxicam

OXICAM DERIVATIVES

• Piroxicam

  • Greatest risk: GI effect

  • Longest half-life

OXICAM DERIVATIVES

• Meloxicam

  • Preferably selective to COX2) 

• Nonseletive

Piroxicam

• Greatest risk: GI effect

• Longest half-life

Meloxicam

Preferably selective to COX2)

Tolmetin

Pyrrole Alkanoic acid derivatives that is C/I to gout

PYRROLE ALKANOIC ACID DERIVATIVES

• COX1 - TXA2

• COX2 - PGI2

Meloxicam

Preferentially selective COX-2 inhibitors

 -coxib, Celecoxib, Etoricoxib, Valdecoxib, Rofecoxib

Highly selective/specific COX-2 inhibitors

Highly selective/specific COX-2 inhibitors

• Advantage: Not associated with GI effects

• Disadvantage: Increase risk or acute thrombotic event = MI, Stroke

Valdecoxib, Rofecoxib

Selective COX-2 Inhibitors that is withdrawn from the market