non sterodial anti inflammatory drugs Flashcards
descibe the Arachidonic Acid Cascade & Eicosanoids
Arachidonic Acid in the celle membrane become the Eicosanoids by the phospholipase A2 and they are converted into lipoxygenesas and cyclooxygenase
a lot of the cyclooxygenase are the prostanoids, it is a pathway molecule
Describe the sythesis of prostanoids
Arachidonic Acid is converted into pgg2 BY COX 1 OR COX2 by process of cyclooxygenase and then into PGH2 by COX1 OR COX2 by process of peroxidase
the PGH2 is converted to other molecules which are major active prostanoids
- TXA2
-PGE2
-PGF2A
-PGI2
-PGD2
What is COX 1
Constitutive in most cells
Homeostasis / Housekeeping
What is COX 2
Inducible by IL-1β and TNF-α
Constitutive in kidney, female
reproductive tract, CNS
what happens when u inhibit COX1 AND COX2
side effects not eleborated by prof
where are the prostanoid receptor located - prostacylcin
endothelum, platelets
where are the prostanoid receptor located - thromboxane A2
platelets, vascular smooeth muscle cells
where are the prostanoid receptor located - prostaglandin D2
mast cellls, lympocytes
where are the prostanoid receptor located - prostaglandin e2
brain,vascular smooeth muscle cells
where are the prostanoid receptor located - prostaglandin f2
yterus, airway, vascular smooeth muscle cells
relaxant type Prostanoid Receptors
IP
EP2
EP4
DP1
Contracitle type Prostanoid Receptors
TP
FP
EP
Inhibitory Type Prostanoid Receptors
EP3
List the biological finctions of Prostacyclin
Vasodilation, inhibit platelet aggregation
List the biological finctions of classical prostaglandins
vascular permeability and pain
List the biological finctions of thromboxane
vacosonstriction and induce platelet aggregation
Biological Roles of Prostanoids(PGI2)
Vasodilatation
Inhibition of platelet aggregation
Renin release
Natriuresis
Biological Roles of Prostanoids(PGD2)
Vasodilatation
Inhibition of platelet aggregation
Bronchoconstriction
Biological Roles of Prostanoids(PGE2)
Vasodilatation
Inhibition of gastric acid secretion
Promotion of gastric cytoprotection
Bronchodilation / bronchoconstriction
Biological Roles of Prostanoids(PGF2A)
Vasoconstriction
Bronchoconstriction
Uterine contraction
Biological Roles of Prostanoids(TXA2)
Vasoconstriction
Promotion of platelet aggregation
Bronchoconstriction
Aspirin machanism
Aspirin inhibits cyclooxygenase (COX-1/2) and
blocks prostanoids production
it is the only NSAID that binds irreversible by
forming covalent bonds with serine residue
What is the Traditional NSAIDs
Act by Inhibition of Cyclooxygenase (COX-1/2)
Anti-inflammatory :: Analgesic :: Antipyretic
How does Aspirin differ from other NSAID
Only Aspirin Irreversibly Acetylates COX by
forming covalent bonds with serine residue
other NSAID: Reversible Steric hindrance blocking
the hydrophobic tunnel via hydrogen
bonding
5 imporatnt NSAID and their half lives
Aspirin(2h)
iduprofen 2h
naproxen 15
paracetamol 2
celecoxib 10
How does the NSAID function as Anti-inflammatory Drugs
XTraditional NSAIDs block:
Vasodilatation, which contributes to
redness, heating and edema
Increased vascular permeability,
which contributes to swelling
Pain associated with inflammation
NSAIDs As Analgesic
PGE2 sensitization of peripheral nociceptive fibres
by blocking cox1/2, reduce the pain transmission
NSAIDs block sensitization, but not direct nociceptive activation, may
explain why NSAIDs have an “Analgesic Ceiling”.– means only can suppress mild pain and if too high, cannot supress
NSAIDs also have additional analgesic action in the CNS
NSAIDs As Antipyretic
when there is Infection, tissue damage, inflammation, Neutrophils release Cytokines (IL-1β, TNF-α),
NSAID block COX1/2
so PGE2 at hypothalamus will not cause Fever
NSAIDs do not alter normal body temperature.
Body’s “thermostat” reset
what is NSAID Use Beyond Inflammation
Aspirin As Anti-platelet Drug
effectve as a blood thinner and prevent heart attack and stroke
under normal condition, the blood fluid and there is TXA2 promotes platelet aggregation,
leading to stroke and heart attack. and PGI2 inhibits platelet
aggregation.
thus when aspirin binds irrevicisbke to COX , TXA2 more than PGI2, it result in blood thinning
list the Adverse Effects of Traditional NSAIDs
GI Tract: N&V, gastric upset, and gastric ulceration, mainly due to COX-1 inhibition: ↓ PGE2
Pseudo-allergic reaction: skin rash, nasal congestion, anaphylactic shock
Bleeding due to blood thinning by aspirin
All non-aspirin NSAIDs have increased risks of heart attack/stroke
Aspirin-linked Reye’s Syndrome in children with viral infection
Aspirin-induced asthma in susceptible asthmatics, associated with viral
URTI
Kidney: acute renal failure, hypernatremia, H2O retention, edema,
hyperkalemia, ↓ glomerular filtration rate (GFR)
Pregnancy toxicity: 1st trimester (risk of miscarriage) and 3rd trimester
(premature closure of ductus arteriosus)
High dose: Dizziness, deafness, tinnitus
what does lipoxygenases do ?
mediator for astma, certain subjects take aspirin and develop asthma
COX-2 Selective Inhibitor
Coxibs
celecoxibs
safer for the gi tract
Limitations of Coxibs
Expectation of complete GI tract sparing with COX-2 selective inhibitors
not realised
Renal toxicity due to constitutive expression of both COX-1 & COX-2 in
the kidney.
Note that all NSAIDs are COX-2 inhibitors:
contraindicated in third trimester of pregnancy causing premature
closure of ductus arteriosus (fetal lung bypass) - patent ductus
arteriosus requires PGE2 production
**Relative increase in TXA2 favours platelet aggregation, which may
increase risk of thrombosis (heart attack and stroke).
COX-2 inhibitors impair wound healing and hence may exacerbate
ulcers - healing requires COX-2 and PGE2.
paracetamol
CNS-selective COX (may be COX-3) inhibitor Anti-pyretic Action, do not have much inflammatory effect, painkiller and lowers fever,
relatively safe
liver converts into p aminophenol
then into AM404 which is a agonist endogenous receptor
analgesic actions
advantages of Paracetamol
Good analgesic
Potent antipyretic
Spares the GI tract
Side-effects few and uncommon
Few drug-drug interactions
Relatively safe for pediatric use
Disadvantages of paracetamol
Weak anti-inflammatory
Toxic doses cause N&V, and
hepatotoxicity by overdose or chronic
alcohol use/abuse
Allergic skin reactions sometimes
occur
