Here, we’ll discuss NSAIDs and acetaminophen, which are the most commonly used anti-inflammatory, anti-pyretic, and over-the-counter analgesic agents.
Here we’ll discuss nsaids and acetaminophen which are the most commonly used anti-inflammatory antipyretic and over-the-counter analgesic agents start a table before we dive into the mechanism and key effects of this class of medications let’s prime ourselves with a simple guide as to how we select which agent to use first to note that for anti-thrombosis for clot
Prevention for heart attack and stroke prevention we prescribe low-dose aspirin the other nsaids can have the opposite effect they can be thrombogenic they can provoke clot formation so they’re generally avoided in patients at risk for thrombotic events next to note that for mild pain or fever acetaminophen and many of the nsaids are used to note that importantly
Acetaminophen is not an anti-inflammatory agent now to note that for moderate to severe pain we use more potent nsaids next specify that in patients at risk for gi ulcer we use acetaminophen and cox-2 inhibitors finally denote that there are a host of nsaids that are used for targeted conditions such as indomethacin for a subset of headaches called hemicranias
Let’s begin our diagram with a review of a section of the cyclooxygenase pathway first draw a section of membrane phospholipids membrane phospholipids are broken down by phospholipase a2 to arachidonic acid then show that arachidonic acid is converted to prostaglandin h2 pgh2 via cyclooxygenase 1 and cyclooxygenase 2. note that in intermediary prostaglandin g2 is
Formed in the process show that prostaglandin h2 is converted to prostaglandin e2 via prostaglandin isomerase thromboxane a2 via thromboxane synthase and prostacyclin pgi2 via prostacyclin synthase show that cyclooxygenase 1 catalyzes prostaglandin and thromboxane production in the normal physiological state for housekeeping mechanisms whereas cyclooxygenase
2 catalyzes it in the inflammatory and cancerous states indicate that prostaglandin e2 prostacycline and thromboxane a2 are all products of the cyclooxygenase 1 pathway whereas on the cycloastronase 2 side both prostaglandin e2 and prostacyclin are produced but thromboxane a2 is not as we’ll see this is an important effect on thrombogenicity now let’s learn
Some of the key effects of these biological mediators so we can understand the indications and risks of nsaids show that nsaids block both cyclooxygenase 1 and 2 whereas selective cyclooxygenase 2 inhibitors also known as cox-2 inhibitors as their name suggests block cycloogenase 2 only indicate that via cyclooxygenase 1 prostaglandin e2 helps protect the gastric
Mucosa and it impacts various aspects of kidney function including afferent blood flow and electrolyte and fluid balance and indicate that via cyclooxygenase to the inflammatory state inflammatory cells produce prostaglandin e2 which produces key inflammatory responses such as fever and pain so indicate that nsaids are used for pain and fever reduction primarily
Through cox 2 inhibition of pge2 next indicate that nsaids inhibit platelet function the clinical impact of these medications on platelets however is much more complicated because of many competing factors in short write that aspirin irreversibly inhibits cox-1 via acetylation which produces prolonged inhibition of platelet aggregation and is thromboprotective
It reduces thrombogenesis but increases bleeding risk whereas non-aspirin cox inhibitors meaning nsaids and selective cox-2 inhibitors produce reversible inhibition of shorter duration and are thrombogenic they promote thrombotic events note however that celecoxib a cox-2 inhibitor has been shown to not increase thrombotic events the exact reason that nsaids
And selective cox2 inhibitors produce thrombogenicity and increase the risk of cardiovascular ischemia has multiple explanations some of which we can understand as follows for background show that thromboxane a2 produces vasoconstriction it increases blood pressure and platelet aggregation whereas prostacyclin produces vasodilation and blocks platelet aggregation
Prostacyclin have multi-fold effects on kidney function thus these two biological mediators balance one another out to avoid unintended clot formation coagulation or bleeding when the vascular endothelium is damaged thromboxane a2 is released to help produce clot formation so one rationale for the increased cardiovascular risk from non-aspirin cox inhibitors is
Imbalanced inhibition of prostacyclin the relative over predominance of thromboxane a2 another rationale has to do with the timing and duration of action of aspirin vs non-aspirin cox inhibitors aspirin produces a prolonged irreversible inhibition of platelet function which is enough to cause a clinical effect whereas the nsaid inhibition of platelet aggregation
Is too short to produce a clinical effect as well non-aspirin cox inhibitors can serve as antagonists of aspirin and thus negate its beneficial effects on the inhibition of clot formation next let’s turn to some of the key risks of nsaids first indicate gastric ulceration so write that ensates can cause gi ulcer because they block the housekeeping activity of
Prostaglandin e2 but selective cox-2 inhibitors should not because they only block prostaglandin e2 in inflammatory or cancerous states they don’t affect the physiological protection of the gastric mucosa right that nsaids can cause renal impairment due to effects on electrolyte and fluid balance and blood pressure now for reasons we’ve already seen indicate that
Nsaids can produce hypertension due to complicated direct vascular and indirect renal effects lastly for completeness indicate that in addition to being thrombogenic nsaids especially aspirin have the risk of causing bleeding now let’s run through some specific aspects of nsaids and acetaminophen as mentioned right that it irreversibly inhibits platelet aggregation
Via covalent acetylation of cyclooxygenase and therefore it provides protection against thrombotic events such as cardiac events or cerebrovascular events right that it has some key additional potential side effects a hypersensitivity reaction note that patients who have nasal polyps are more likely to suffer from this as well it can produce asthma or tinnitus
Right that it can cause severe acute reactions such as aspirin overdose salicylate overdose can cause metabolic derangement fever and hyperventilation as well as rhabdomyolysis and renal failure and cerebral edema and seizures and it can cause rye syndrome which is a rare life-threatening disorder that classically occurs in children who take aspirin in the setting
Of a current or recent viral illness it manifests with cerebral edema and hepatic failure for the numerous other nsaids we’ve already addressed their typical potential side effects so let’s just list their common uses which include the treatment of pain arthritis gout dysmenorrhea migraine patent ductus arteriosus and premature infants and cancer prevention now
For the cox-2 selective inhibitors indicate that the major advantage is that they avoid gi ulcers but note that they still can cause renal impairment also point out that celecoxib does not increase the risk of thrombotic events now let’s look at acetaminophen indicate that it’s a weak peripheral cox-1 and cox-2 inhibitor and that it has no anti-inflammatory
Effects it’s proposed that it acts via cox-3 inhibition in the central nervous system thus indicate that it’s preferred over nsaids in patients with hemophilia gi ulcer and aspirin hypersensitivities amongst other conditions write that in acetaminophen metabolism if glutathione is depleted napqi a potentially toxic metabolic intermediary binds to cellular
Proteins to form hepatotoxic metabolites let’s take a close look at how this toxicity can form show that acetaminophen has some safe metabolic pathways to form non-toxic products it can undergo sulfation or glucuronidation to form non-toxic products or it can undergo p450 metabolism most commonly cyp2 metabolism to form napqi which can form non-toxic products
Via glutathione conjugation cysteine and mercatoric acid conjugates however if glutathione stores are depleted or overwhelmed then napqi can bind cellular proteins to form toxic byproducts that produce hepatotoxicity thus indicate that in cases of acetaminophen overdose we administer an acetylcysteine to replenish glutathione stores to try to shunt napqi through
Glutathione conjugation rather than form toxic metabolites consider that patients with any of the following will have an increased risk of acetaminophen toxicity a reduced capacity for glucuronidation or sulfation glutathione deficiency such as from liver failure or malnutrition or cyp2e1 induction such as from use of isoniazid or chronic ethanol use this concludes our diagram
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NSAIDS & ACETAMINOPHEN By Draw it to Know it – Medical \u0026 Biological Sciences
