Major Prostaglandins
Prostanoid Acid and PGI2 (Prostacyclin)
Prostaglandin Synthases
Cox 1 - Constitutive
Cox 2 - Induced
NSAIDs
Analgesic Anti-pyretic Anti-inflammatory All inhibit COX (Some may inhibit LOX) Short-term relief
Salicylic Acid Derivatives
ASA
Diflunisal
Par-aminophenol Derivatives
Acetaminophen (Not Anti-Inflammatory)
Indole and Irdene Acetic Acids
Etodolac
Heteroaryl Acetic Acids
Diclofenac
Ketorolac
Arylpropionic Acid
Ibuprofen
Naproxen
Flurbiprofen
Ketoprofen
Anthraniic Acids (Fenamates)
Mefanamic Acid
Enolic Acids
Mecloxicam
Alkanones
Nabumetone
Diarylheterocycles (COX2 Selective Inhibitors)
Celecoxib
Prostaglandin
Hyperalgesia
Allodynia
Spontaneous pain
Aspirin
Irreversible acetylation of serene in active site of both cyclo-oxygenases; Acetylation of COX2 alters enzymatic action to produce 15-epi-lipoxins and resolvins
May induce asthma
Anaphylactoid reaction: Arachidonic acid to Prostaglandin (COX inhibit) switch to Leukotrienes (LOX)
NSAID Platelet Function
Blocks
Aspirin - Irreversible block of thromboxane synthesis in platelets and effect lasts until new platelets form (7days); NSAID - Reversibly inhibits COX so short term thromboxane effect
COX2 inhibitors - Reduce PGI2 protective effect, Blood clots, Cardiac arrest, Death (Inhibit COX2 in endothelial cells - Reduce beneficial vasodilatory activity of PGI2 and prevent platelet aggregation (No effect on COX1)
NSAID Renal Function
PG and Renin regulate renal blood flow - NSAID alter salt retention and hypertension by reducing blood flow
Prostaglandin Fever
Pyrogen to Cytokines - Increase COX2 - mPGES1 - Increase PGE2 - Activate EP3 receptor in hypothalamus - Increase efferent outflow (Muscles, Sweat glands, Brown adipose tissue)
COX-2 Inhibitors
GI cytoprotection - COX1
Inflammatory response - COX2
COX 2 -> Reduce GI disturbance
COX 2 Selective Analgesics - Cardiovascular effects due to no action on platelets (COX-1) but significant effect on PGI2 production in endothelium, Increased heart attack and stroke; Adverse effect on resolvin production; Negative effect on bone healing
Current COX-2 Inhibitors
Celecoxib (Celebrex)
Rofecoxib (Vioxx) GONE
Etoricoxib (Arcoxia) EUROPE
Lumiracoxib (Prexige) MEXICO, UK
NSAID Bone Healing
Prostanoid production normal in would healing, fracture repair
NSAID - slow fracture reapir (COX2) poorer repair and worsening of radiological joint deterioration
Reduced bone healing - Reduced diff of mesenchymal cells to osteoblasts - Reduced activity of transcription factors essential for osteoblastogenesis - COX 2 +BMP osteoclast formation blocked
Retard ortho movement; Extraction bone repair; Implant osteo-integration; Reduce periodontal inflammation and bone loss
Reyes Syndrome
Influenza and Salicilate (Aspirin, Pepto-Bismol, Difunisal); Stage I - Vomit, Brain dysfunction, Energy loss; Stage II - Irritability; Stage III - Confusion, Combative; Vomiting Elevated blood NH3 Hypoglycemia and Hepatomegaly DONT USE ASPIRIN ON KIDS
Prostaglandin Gender
Obstetrics: Promote cervical ripening, Induce labor, Induce abortion; Misoprostol (Cytotec) - GI, Uterine; Post delivery - Post partum hemorrhage; PG maintain ductus arteriosus - Premature close of DA; Avoid in pregnancy; Breast feeding - Naproxen or Ibuprofen analgesic do not enter breast milk
Non-Antiinflammatory Analgesic
Phenacetin
Acetaminophen
Acetaminophen
Only low O2 environment - Brain; Affects Peroxidase site
Anaglesic, Anti-pyretic, Little anti-inflammatory, Doesn’t interfere with tooth movement or implant osteo-integration, Few GI adverse effects, Few renal adverse effects, No platelet function alter, In children, In pregnancy
Acetaminophen Hepatotoxicity
Metabolism of acetaminophen to N-acetyl-para-benzoquinoneimine; Worse by alcohol
Acetaminophen to NAPQI to Mercaptopuric acid (w/GSH)
Limit GSH - NAPQI to toxic
Zileuton
Specific 5-lipoxygenase inhibitor, Mild persistent asthma, Effective as inhaled glucocorticoids, Inhibit numerous P450
Zafirlukast
Montelukast (Singulair)
LTD4 receptor antagonist
Effective as Zileuton - Fewer drug interactions
Headache, Hepatic enzyme elevation
DMAARDS
Disease Modifying Anti Arthritic Drugs
Anti-TNF Drugs or Anti-IL
Cimzia, Enbrel, Humira, Remicade, Simponi, Kineret, Actemra, Orencia, Rituxan
But injection site reactions, Immune dysfunction, Infections and Very High cost
