NSAIDs Flashcards
What are the general indication for the NSAID drugs?
Pain Relief
Reduction of inflammation
Reduction of fever
What are some of the aspirin specific indications?
Stroke/MI prevention
Inhibition of Platelet activation
What is the general mechanism of NSAIDs?
They inhibit cyclooxygenases which are the rate limiting enzyme in the synthesis of prostaglandins, which are one of the mediators of the pain/inflammatory/fever response
What is the mechanism of COX enzyme inhibition of NSAIDs?
They are competitive antagonists of arachidonic acid substrate in the active site of COX which prevents the synthesis of PGs.
What is aspirin’s mechanism of action and why is it unique?
It is unique because it acts as an irreversible non-competitive COX enzyme inhibitor
What is the function of COX1/2?
Catalyze the conversion of arachidonic acid into prostaglandins and thromboxane
What is the expression of COX1 and where is it expressed?
COX1 is expressed in most tissues constitutively for general housekeeping functions
What is the expression of COX2 and where is it expressed?
It is under inducible expression to pro inflammatory stimuli and it is expressed in the kidney and the endothelium constitutively and in monocytes and macrophages under induction.
What is the main factor that causes the adverse effects of NSAIDs?
Inhibition of the constitutive expression of COX1
What are the types of NSAIDs?
a) Aspirin and salicylates
b) Traditional NSAIDs
c) COX-2 specific inhibitors
What is the function of prostaglandins?
Do not generate pain responses but they increase the responses to painful stimuli
What is the action of aspirin on the COX enzymes?
It covalently attaches an acetyl group to the active site of COX enzymes irreversibly inhibiting COX-1 activity. Note aspirin also acetylates COX-2, but because the active site of COX-2 is larger and more flexible arachidonic acid can still gain access to the active site, albeit less efficiently- hence aspirin is a less potent inhibitor of COX-2 than COX-1.
What is the function of COX1 in the stomach?
In the stomach, it produces PGs which are protective for the cells facing the acid of the stomach.
What is the function of COX1 in the blood?
It is important in the determination of the balance between TXA2 and PGI2 which determines constriction and clotting.
What is the function of COX2 in the kidney?
Prostaglandins that are produced by COX2 cause vasodilation which prevents renal ischemia
What is the function of COX enzymes in pregnancy?
PGs that are made stimulate uterine contraction so NSAIDs can delay labor
What is the use of NSAIDs in the newborn?
They can be used to trigger the closure of a patent ductus arteriosus
How is aspirin absorbed in the stomach?
In the stomach, the low pH will protonate it into an uncharged from that can cross easily into the plasma
What happens to aspirin absorbed into the plasma?
It is metabolized to salicylic acid and acetic acid which lead to the inhibition of COX1 and 2
How do low doses of aspirin prevent MI and stroke?
Aspirin enacts a strong effect on COX1 inhibiting it irreversibly which prevents TXA2 by the platelets which cannot regenerate COX1. PGI2 is not as affected at low doses because endothelial cells can regenerate COX1 to make PGI2. This leads to an environment where vasodilation and inhibition of platelet aggregation is favored.
What is the function of TXA2 and what is it made by?
Platelet COX1
Vasoconstriction and prothrombogenic
What is the function of PGI2 and what is it made by?
Endothelial COX1
Vasodilation and inhibition of platelet aggregation
Why do other NSAIDs not have the sam prophylactic function as aspirin?
They have similar functions, but due to the fact that their inhibition on the COX1 enzyme is reversible, they are not as effective.
When are the other salicylates used?
They have lower risks of side effects than aspirin so they are preferable in patients with bleeding or GI complications
What are the characteristics of the traditional NSAIDs?
They are all non-selective competitive inhibitors of COX enzymes
What is an additional use for tNSAIDs that aspirin did not have?
Treatment of gout
What is the most common NSAID side effect?
GI toxicity
What can be co-administered to minimize the effect of NSAID GI toxicity?
Misprostol
Omeprazole
What can be a side effect of NSAIDs on the kidneys?
It can cause renal failure due to the inhibition of COX2 which will decrease the PGs and lead to vasoconstriction and ischemia of the kidney. This is not seen in normal patients but in patients already presenting with renal problems.
What can be a side effect of NSAIDs on the CV system?
It can cause a small increase in the risk of MI and stroke
What can be a side effect of NSAIDs on HTN?
It can exacerbate HTN because at high doses, vasoconstriction can result due to the decreased PG vasodilatory effect
What can be a side effect of NSAIDs on hemorrhage?
Anti-platelet activity can cause increased risk of bleeding
What is NSAID hypersensitivity?
In a minority population, NSAIDs can cause acute asthma attacks
What are possible side effects with using aspirin in children?
Reye’s Syndrome - causes liver degeneration
What is another risk unique to aspirin?
Increasing the risk for gout as aspirin can inhibit the excretion of uric acid in the kidney
What is the mechanism of coxibs?
Coxibs are selective for inhibition of COX2 with minimal COX1 inhibition
What are some good uses for coxib drugs like celecoxib?
Rheumatoid Arthritis
Osteoarthritis
Those with bleeding or GI problems like ulcers that would not tolerate COX1 inhibition well
What are some adverse effects of COX2-selective drugs?
They show increased risk for CV events and should not be used by those with a history of CV disease.
COX2 in the endothelium being inhibited causes PGI2 levels to decreased, leading to increased vasoconstriction and platelet aggregation.
What is the interaction between low dose aspirin and NSAIDs?
NSAIDs will impair the effect of aspirin via competitive antagonism
What is the interaction between methotrexate and NSAIDs?
It will impair kidney excretion of methotrexate and lead to toxicity
What is the interaction of HTN drugs and NSAIDs?
NSAIDs promote renal vasoconstriction which counteracts anti-hypertensive effects of drugs
What is the interaction of salicylates and sulfonylureas?
Salicylates displace protein-bound sulfonylureas and independently enhance glucose utilization which potentiate hypoglycemic effects of sulfonylureas
What is acetaminophen used for?
Treatment of pain and fever with NO effect on inflammation or platelets
What is the mechanism of acetaminophen?
It works centrally on the CNS and it does not effectively inhibit either COX-1 or COX-2 expressed in the periphery.
It is metabolized to AM404 in the brain which inhibits COX2 as well as acting on the endogenous cannabinoid system in the pain and thermoregulatory centers of the CNS to reduce pain and fever
Why does acetaminophen have little inhibition of the COX in the periphery?
High concentration hydroperoxides which oxidize COX and keep it in the active state.
What can an overdose of acetaminophen cause and how?
It can cause hepatic toxicity via increased levels of toxic NAPQI
What is the antidote to acetaminophen overdose and how does it work?
N-acetylcysteine.
It replenishes endogenous glutathione levels which can convert NAPQI to a non-toxic metabolite
What are patients where acetaminophen would be preferred?
a) patients that are allergic to Aspirin or other Salicylates
b) Children with viral infections- to avoid Reye’s syndrome associated with Aspirin
c) Patients with hemophilia or increased risk of bleeding
d) Patients with a prior history of gastric/peptic ulcers
