L18 and L19 NSAIDS Flashcards
inflammation
-Occurs upon infections or noxious stimuli.
-Eliminates harmful agents (e.g. microbes, toxins) and necrotic cells.
-Initiates the healing process.
-May injure normal tissues
how may an infection injure normal tissues
-Too strong response (severe infection)
-Prolonged response (persistent or recurrent infection)
-inappropriate response (self-antigens in autoimmune diseases)
signs of inflammation
-Heat (calor)
-Redness (rubor)
-Swelling (tumor)
-Pain (dolor)
-Loss of function (functio laesa)
chemical mediator of inflammation
-vasoactive amines
-eicosandoids
-platelet-activating factor (PAF)
-cytokines
-complement components
-coagulation and kinin systems
what are kinds of eicosanoids of inflammation
protaglandins, leukotrienes, and lipoxins
what are vasoactive amines of inflammation
histamines and sertonin
what are cytokines that cause acute inflammation
-tumor necrosis factor (TNF), interleukin-1 (IL-1), chemokines
what are the chemokine that cuase chronic inflammation
interferon-y (IFN-y)
what are the kinds of complement compounds of inflammation
C3a and C5a
what are the coagulation and kinin systems of inflammation
bradykinin, thrombin, and fibrinopeptides
eicosanoid
-short lived mediators (second to minutes)
-autocrine and paracrine signaling
-bind to G-proteins coupled receptors (GPCRs) in the target cells
*generation of cAMP (Gs)–> dilation
* release of calcium (Gq)–> constriction
eicosanoid: PGE2
-dilation of blood vessels, bronchi
-oxytocic dilation in uterus
eicosanoids: PGF2a
-constriction of blood vessels, bronchi
-oxytocic constriction of uterus
eicosanoids: PGI2
-dilation of blood vessels
-inhibits aggregation in platelets
eicosanoids: TXA2
-constriction of blood vessels
-aggregation of platelets
arachidonic acids
-20-carbon polyunsaturated fatty acids
-Essential fatty acids
-Most abundant and important precursor of eicosanoids
-Released from membrane phospholipids by phospholipase A2 (PLA 2 ).
-Corticosteroids suppresses the production of phospholipase A2 .
oxygenation of arachidonic acid
-PGH synthase (COX) pathway
-Lipoxygenase pathway
-Epoxygenase (cytochrome p450) pathway
-Isoprostane pathway (free radical reaction
PGH synthase
-PGH synthase has both cyclooxygenase and hydroperoxidase activities.
-Cyclooxygenase (COX) reaction
*Radical-mediated oxidation
-Hydroperoxidase reaction
*Conversion of a hydroperoxyl group (-OOH) to a hydroxyl group (-OH
what are the two isoforms of PGH synthase
-PGH synthase 1
-PGH synthase 2
-inhibited by nonsteridal anti inflammatory drugs (NSAIDS)
PGH synthase 1
-COX-1
-Constitutively expressed in various tissues.
-“Housekeeping” functions, e.g. gastric cytoprotection
PGH synthase 2
-COX-2
-Expressed upon stimulus in inflammatory and immune cells.
-Stimulated by growth factors, tumor promoters, and cytokines.
alprostadil
-eicosanoid drug
-PGE 1
-Relaxes smooth muscles and expand blood
vessels.
-used for erectile dysfunction by injection or as a suppository
misoprostol
-eicosanoid drug
-PG F 1 derivative
-cytoprotective
-prevents peptic ulcers
-terminated early pregnancy in combination with mifeprestone
latanoprost
-eicosanoid drug
-Topically active PGF 2a derivative (prodrug)
-Constrict blood vessels.
-Used in ophthalmology to treat high pressure
inside the eye (ex. glaucoma)
prostacyclin
-eicosanoid drug
-PGI 2
-Powerful vasodilator
-Inhibitor of platelet aggregation
-Used to treat pulmonary arterial hypertension
by IV injection or inhalation.
-Should not be used with anticoagulants.
activites of NSAIDs
-Anti-inflammatory
-Analgesic
-Antipyretic
uses of NSAIDs
-Treatment of moderate pain, fever, and inflammation from acute inflammation
-Treatment of early-stage rheumatoid arthritis and osteoarthritis
-Cancer preventio
mechanisms of action NSAIDs
-Inhibition of prostaglandin endoperoxide H synthase (PGHS or COX), which catalyzes the formation of prostaglandins.
-Many NSAIDs inhibit both COX-1 and COX-2
classes of NSAIDs
-salicylates
-arylacetic acids
-arylpropionic acids
-non carboxylase NSAIDs
-COX 2 selective NSAIDs
Gastrointestinal side effects of NSAIDs
-Mild (common): dyspepsia, nausea, vomiting
-severe (rare: blood loss, ulcer, GI hemorrhage
-administration with food may decreases GI side effects.
-Aspirin ~ indomethacin > naproxen > sulindac
mechanisms of gastrointestinal effects of NSAIDs
-Acidity of many NSAID –> primary insult
-Inhibition of synthesis of cytoprotective prostaglandins (PGEs) in gastric mucosa->secondary insult
-Inhibition of platelet aggregation (increased tendency of bleeding)
blood coagulation side effects of NSAIDs
-Aspirin prolongs bleeding time by irreversible inhibition of platelet COX-1 and the consequent reduced formation of thromboxane.
-Aspirin use before surgery or tooth extraction is contraindicated.
-can be used to some patients with cardiovascular disease to prevent blood
coagulation.
renal side effects of NSAIDs
-Little effect in normal patients.
-Renal failure in patients with cardiovascular, hepatic, and renal diseases
Hypersensitivity side effects of NSAIDs
-Characterized by skin rashes, hives, angioedema, and an asthma-like syndrome
(blocked by 5-lipoxygenase inhibitors).
-Occurs in 0.3% of the population (10% in asthmatics).
reye’s side effects of NSAIDs
-specific to salicylates
-A rare, acute, life-threatening condition characterized by vomiting, delirium, an coma (20-30% mortality)
-Brain damage is common in survivors.
-Occurs in children who have had the flu or chicken pox.
-Aspirin should not be given to anyone under the age of 12 who has a fever
CNS side effects of NSAIDs
-Tinnitus
-Dizziness
-Headache
misoprostol prevention of GI side effects
-Synthetic PGE1 analog
-Used prophylactically to prevent NSAID-induced gastric ulcers in patients at high risk
Proton pump inhibitors (e.g. esomeprazole) prevention of GI side effects
-Greatly reduce acid secretion in stomach and protect against ulceration in the
absence of COX-1 activity.
drug interactions of NSAIDs
-Many NSAIDs are highly bound to serum albumin (typically 90-99%).
-NSAIDs may compete for serum albumin binding sites with other drugs that are
highly bound to these sites
combination products to prevent GI side effects
-Naproxen/esomeprazole
-Naproxen/misoprostol
-Diclofenac/misoprosto
examples of drug interactions of NSAIDs
– combination with oral anticoagulants
-Increases the plasma concentration of free anticoagulant.
-The ability of salicylate to produce GI bleeding and inhibit the clotting mechanism aggravates the problem.
-Necessitates a possible decrease in the dosage of anticoagulant
structure activity relationships in NSAIDs
-Commonly contains an acidic group (e.g. carboxylic acid)
-the acidic group is located one carbon atom adjacent to an aromatic or heteroaromatic ring.
-Substitution of a methyl group on the carbon atom separating the acidic group from the aromatic ring (acetyl propionic) tends to increase activity (“profens”).
-A second area of lipophilicity (aromatic or alkyl) that is noncoplanar with the aromatic or heteroaromatic ring generally enhances activity
salicylates
-salicylic acid
-aspirin
-salsalate
-disunisal
salicylic acid
-salicylate
-First obtained in 1838 from salicin, a glycoside present in willow and poplar bark (from Latin salix, willow tree).
-Hippocrates prescribed chewing willow bark for pain relief in the 5th century BC (no formal record).
-Sodium salicylate was used as an antipyretic /antirheumatic agent in 1875.
-Slightly acidic (pKa = 3.0)
-absorbed as an ionic form from the small intestine and, to lesser extent, from the stomach as an acid form.
-Inhibits COX-1 and COX-2 reversibly.
-May suppress COX-2 induction.
aspirin (acetylsalicylic acid)
-salicylate
-prepared in 1853 but was used as a drug in 1899.
-The only NSAID that irreversibly inhibits COX by acetylating a serine residue in the active site.
-Absorbed largely as the intact form but hydrolyzed rapidly to salicylate by plasma esterase.
-2-fold more potent than salicylic acid as analgesic/antipyretic.
-Blocks platelet-aggregating factor TXA 2 effectively; increases the risk of bleeding
but also reduces the risk of myocardial infarction.
-Not stable in solutions
salsalate
-salicylate
-Dimer of salicylic acid
-Hydrolyzed to two salicylates in the small intestine and absorbed.
-Does not cause GI bleedin
diflunisal
-salicylates
-More potent analgesic than aspirin, but produces fewer side effects.
-Less antipyretic activity than aspirin.
-3-4 fold longer t 1/2 than aspiri
arylacetic acids
-indomethacin
-sulindac
-etodolac
-diclofenac
indomethacin
-One of the most potent NSAIDS in use
-High incidence of side effects
-Not suitable for a long-term use.
-Not stable in solution due to the hydrolysis of the amide bond.
sulindac
-Prodrug; the sulfoxide group is reduced to the active sulfide intermediate in the circulatory
system.
-Less GI side effects.
-Suitable for a long-term use to treat chronic inflammation
etodolac
-Pyranocarboxylic acid
-As potent as indomethacin.
-Somewhat selective for COX-2.
-Less GI bleeding
-suitable for long-term use to manage osteoarthritis
diclofenac
-The most widely used NSAID in the world.
-As potent as indomethacin
-Somewhat selective for COX-2.
-inhibits both COX and lipoxygenase pathways
arylpropionic acid
-ibuprofen
-naproxen
-ketorolac
ibuprofen
-Popular OTC analgesic
-More potent than aspirin, but less potent than indomethacin.
-Moderate degrees of gastric irritation
-α-Methyl group enhances it activity and reduces many side effects.
-Bioequivalent racemic mixture
-S-(+)-enantiomer possesses greater activity in vitro.
-R-(-)-enantiomer is converted to S-(+)-enantiomer enzymatically in vivo.
ketorolac
-Cyclized heteroarylpropionic acid derivative
-Short-term management of moderate to severe pain.
-Analgesic activity similar to centrally acting analgesics.
-Widely accepted alternative to narcotic analgesics.
naproxen
-S-(+)-enantiomer
-More potent than ibuprofen.
-Moderate degrees of gastric irritation.
-Used to treat rheumatoid arthritis and osteoarthritis
non-carbocylates
-nabumetone
-meloxicam
nabumetone
-Nonacidic prodrug
-Metabolized rapidly to 6-methoxynaphthalene-acetic acid (6-MNA), which is an effective inhibitor
of COX.
-Minimum gastric side effects.
-Potent anti-inflammatory, but weak analgesic activity
meloxicam
-Belongs to the oxicam class, which resembles the peroxy radical intermediate in COX.
-Enolic acid
-Long acting; single daily dose.
-As potent as indomethacin.
-Somewhat selective for COX-2
consequences of COX-1 inhibition
-Stomach irritation and ulceration
*Decreased production of cytoprotective prostaglandins
*Bleeding from inhibition of thromboxane formation
-Blockade of platelet aggregation
-inhibition of uterine motility
-Inhibition of prostaglandin-mediated renal function
-Hypersensitivity reactions
-Preferential inhibition of COX-2 gives anti-inflammatory effects with lower incidence of gastric ulceration
selectivity COX-2 inhibitors
-Valine in the NSAID binding site of COX-2 is substituted for isoluecine in that of COX-1.
-Selective COX-2 inhibitors exploit the larger NSAID binding site in COX-2 with larger and relatively rigid substituents.
-FDA classifies only celecoxib, rofecoxib, and valdecoxib as selective COX-2 inhibitors (“coxib”)
side effects of selectivity COX-2 inhibitors
-Selective inhibition of COX-2 results in elevated
blood pressure and accelerated atherogenesis.
-Constitutive expression of COX-2 in endothelium is critical for production of PGI2 (prostacyclin)
-selective COX-2 inhibitors do not affect the
production of TXA2 by COX-1; heightened
thrombotic response on the rupture of
atherosclerotic plaque.
-Selective COX-2 inhibitors increase
cardiovascular hazard (heart attack and stroke).
-Merck withdrew rofecoxib from the US market
in 2004.
-Pfizer withdrew valdecoxib from the US market
in 2005.
celecoxib
-First NSAID to be marketed as selective COX-2 inhibitor.
-Used for osteoarthritis and rheumatoid arthritis.
-Good efficacy against pain, inflammation, and fever.
-As potent as naproxen.
-Less risk of GI side effects.
-No antiplatelet activity
activities of acetaminophen
-Analgesic and antipyretic effects similar to aspirin.
-Much weaker as an anti-inflammatory agent
mechanisms of action of acetaminophen
-Does not inhibit arachidonic acid binding to PGHS.
-Scavenges peroxynitrite required for PGH synthase activity.
-Peroxynitrite is the major oxidant for PGH synthase activity in the CNS.
-In inflammation, high concentrations of peroxides are present, and
acetaminophen scavenging is overwhelmed
fewer adverse effects compared to aspirin
-Lower incidence of gastrointestinal disturbance.
-Tolerated in patients with blood coagulation disorders.
-Not associated with Reye’s syndrome.
-May cause a rash but a low incidence of hypersensitivity.
-Does not cross-react with aspirin
hepatoxicity at toxic dose acetaminophen
-Cytochrome P450-mediated N-hydroxylation to form N-acetylimidoquinone,
which reacts with glutathione.
-toxic doses overload the glutathione, and cell damage occurs in the liver.
eicosanoids
-Alprostadil (Edex®)
-Misoprostol (Cytotec®)
-Latanoprost (Xalatan® , Monopost ®)
-Prostacyclin (Epoprostenol ®
salicylates
-Salicylic acid
-Aspirin
-Salsalate (Disalcid®)
-Diflunisal (Dolobid ®
arylacetics acids
-Indomethacin (Indocin®, Tivorbex®)
-Sulindac (Clinoril ®)
-Etodolac (Lodine®)
-Diclofenac (Cataflam® ,Voltaren®
arylpropioic acids
-Ibuprofen (Advil ®, Motrin®)
-Naproxen (Aleve ®)
-Ketorolac (Toradol ®, Biorolac®
Selective COX-2 inhibitor
Celecoxib (Celebrex ®)
non-carboxylates
-Nabumetone (Relafen®)
-Meloxicam (Mobic®, Vivlodex®)
