Non-steroidal anti-inflammatory drugs

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Introduction0:00–0:27

Non-steroidal anti-inflammatory drugs or NSAIDs are mainly used to treat inflammation, pain, and fever. These conditions are related to an increased production of pro-inflammatory chemicals called prostaglandins.
NSAIDs work by decreasing the production of prostaglandins, thereby reducing inflammation, relieving pain, and reducing fever.

Physiology0:27–2:06

In order to understand how NSAIDs work, first we need to talk briefly about inflammation, which is the body’s response to a harmful stimulus, such as infection or injury.
So, during inflammation, your immune cells use an enzyme called phospholipase A2 to take membrane phospholipids and make a 20-carbon polyunsaturated fatty acid, called arachidonic acid.
Arachidonic acid is a substrate for an enzyme called cyclooxygenase or COX. The enzyme cyclooxygenase exists in two different isoforms: COX-1 and COX-2.
COX-1 is a constitutive enzyme, meaning that it’s always active, while on the other hand, COX-2 is an inducible enzyme, meaning that it must be turned on to function.
This is usually triggered by immune cells and vascular endothelial cells during inflammation. Both enzymes produce prostaglandin E2 (PGE2) and prostacyclin (PGI2), which cause vasodilation and attract different immune cells to the area.
They also act on neurons that detect pain, called nociceptors, and make them more sensitive to stimuli by lowering their threshold for activation.
Finally, they stimulate the hypothalamus to increase the body temperature, causing fever. Prostaglandin E2 also has other effects like causing uterine contractions, decreasing the secretion of acid, and increasing the production of protective mucus in the stomach.
So, in conditions such as inflammation, pain, or fever, NSAIDs can be used to inhibit cyclooxygenase and decrease the production of prostaglandins.

Mechanism of Action2:06–2:43

Depending on how they interact with these enzymes, NSAIDs are subdivided into 2 main groups: irreversible COX inhibitors, like aspirin; and reversible COX inhibitors, or non-aspirin NSAIDs.
Non-aspirin NSAIDs can be further subdivided into 2 groups: non-selective COX inhibitors, which include common medications like ibuprofen, and selective COX-2 inhibitors like celecoxib.
Alright, now let’s start with aspirin, also known as acetylsalicylic acid, which works by irreversibly inhibiting both COX-1 and COX-2.

Aspirin2:43–4:52

Aspirin is taken perorally and most of the absorption occurs in the ileum. Once absorbed into the bloodstream, aspirin irreversibly inhibits COX-1 in platelets by covalent acetylation, thereby decreasing production of thromboxane A2 in platelets.
Since thromboxane A2 is a platelet activator, this makes aspirin useful as an antiplatelet medication. Since aspirin irreversibly prevents the platelets from synthesizing new COX-1 enzymes, aspirin’s effect will persist until there are enough new platelets produced that are able to produce COX-1 enzymes.
This leads to increased bleeding time without affecting PT or PTT. Next, in the liver, aspirin is metabolized into salicylate, which doesn’t have the antiplatelet effect, but it does have anti-inflammatory properties.
Salicylate works by inhibiting COX-2, thereby reducing prostaglandin production, leading to decreased inflammation, pain, and fever; so, it’s commonly used to treat headaches and musculoskeletal pain.
It’s also used for the short term treatment of chronic pain like osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis.
It’s important to note that the effects of aspirin are dose-dependent: low doses under 300 mg/day work as an antiplatelet medication; medium doses between 300 and 2400 mg/day work as an antipyretic and analgesic; and high doses over 2400 mg/day work as an anti-inflammatory medication.
Low doses or “baby aspirin” in the form of 81 mg tablets are used long-term to help prevent heart attacks, strokes, and blood clot formation in people at high risk of developing blood clots.
Okay, moving on to non-selective COX inhibitors, which reversibly inhibit both COX-1 and COX-2. Common medications in this class include ibuprofen, naproxen, ketorolac, indomethacin, sulindac, meloxicam, and many others.

Non-selective COX inhibitors4:52–6:22

All these medications can be taken perorally, but ketorolac, ibuprofen, and indomethacin are the only NSAIDs that are also available in parenteral form.
Just like aspirin, these medications also inhibit COX-1 and have an antiplatelet effect, but because they’re reversible inhibitors, their effect is transient so they won’t provide the same benefit as aspirin.
If taken together with aspirin, they will even compete for the binding sites on COX-1, which results in a decrease in the antiplatelet effect of aspirin.
Next, these medications also inhibit COX-2, which reduces inflammation, pain, and fever, so they have the same indications as aspirin.
However, ibuprofen, naproxen, and indomethacin are also used to reduce inflammation during an acute gout attack, where aspirin should be avoided since it competes with uric acid for excretion in the kidneys, which might worsen the symptoms of gout.
Indomethacin is also used to close patent ductus arteriosus in neonates and premature infants, while ketorolac is used to treat severe acute pain, usually after surgery.

Selective COX-2 inhibitors6:22–6:54

Now moving on to selective COX-2 inhibitors, the main medication in this group is celecoxib. Celecoxib reversibly inhibits COX-2, so it can treat pain and inflammation like the other NSAIDs.
Since it doesn’t affect COX-1, it lacks the antiplatelet effect seen in aspirin. On the other hand, it doesn’t compete with aspirin for COX-1 like the reversible nonselective COX inhibitors, so it can be combined with aspirin without decreasing its antiplatelet effect.

Side Effects6:54–10:56

For side effects, both aspirin and the nonselective COX inhibitors can cause problems by blocking COX-1 in many parts of the body.
Inhibition of COX-1 in the stomach decreases the concentration of cytoprotective prostaglandins, which can lead to gastritis, gastric ulcers, or even bleeding.
Reversible inhibitors of COX-1 cause less gastrointestinal problems when compared to aspirin, and selective COX-2 inhibitors like celecoxib causes the least GI side effects since they don’t affect COX-1.
In the kidneys, all NSAIDs inhibit COX-2. which decreases the level of prostaglandins that dilate the renal artery, causing a reduction in renal blood flow.
This reduced blood flow tricks the kidney into thinking the blood pressure is low, so in order to increase it, they activate the renin-angiotensin-aldosterone system, which can lead to hypertension.
An interesting fact is that low doses of aspirin can actually lower the blood pressure, but only if taken right before bed time.
The mechanism behind this is still being studied, but high doses of aspirin will increase blood pressure like all the other NSAIDs.
Now when the blood flow to the kidney is reduced it can lead to acute kidney injury, which is particularly true in the elderly and individuals with underlying heart, liver, or kidney disease.
In addition, chronic abuse of NSAIDs in these individuals can lead to analgesic nephropathy, which can manifest as chronic nephritis or renal papillary necrosis.
Other side effects include hypersensitivity reactions that could lead to side effects such as Stevens-Johnson Syndrome, toxic epidermal necrolysis, and anaphylactic reactions.
It’s important to note that individuals who experience hypersensitivity to one NSAID, can also experience the same reaction when taking other NSAIDs due to cross-hypersensitivity.
People with nasal polyps and asthma are also more likely to experience NSAID hypersensitivity, and these three together are called Samter’s triad, or aspirin exacerbated respiratory disease.
For medicine-specific side effects, aspirin needs special attention. First, it should not be given to reduce fever in children with viral infections, as it can lead to Reye’s syndrome, which is a condition characterized by liver damage and progressive encephalopathy.
However, aspirin can be used in children to reduce fever is Kawasaki’s disease. Next, an aspirin overdose can be fatal.
Early symptoms of salicylate poisoning include tinnitus, deafness, headache, and vomiting; while at high doses, salicylate can directly stimulate the respiratory center and cause hyperventilation and respiratory alkalosis.
Moreover, as the dose increases, salicylates start to inhibit oxidative phosphorylation, which is used to generate energy in the aerobic pathway.
So the body switches to the anaerobic pathway which produces lactic acid, and the increase in lactic acid eventually causes an elevated anion gap metabolic acidosis.
As blood pH decreases, salicylate shifts more towards its non-ionized form, salicylic acid, which easily crosses the blood-brain barrier and causes seizures or even coma.
It’s important to note that there's no specific antidote for aspirin overdose, instead, treatment includes administration of activated charcoal, which binds aspirin and prevents its absorption in the GI tract; alkalization of urine by sodium bicarbonate, which facilitates salicylate excretion; ventilatory support; and the management of the acid-base imbalance.
Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharm facts! So let’s use a chicken farm full of roosters, or cocks, for the NSAIDs, which inhibit COX enzymes.

Memory Palace10:56–15:13

Now, in the first coop, there are two dead roosters: one with two heads for COX-2, and one with a single head for COX-1.
These roosters are dead to help you remember this coop contains the non-reversible COX inhibitors. What killed both of these chickens are 2 giant springs, representing aspirin, and you can see them sticking out of the rooster’s chests.
For indications, let’s have the chicken’s dinner plate broken into pieces to represent aspirin’s antiplatelet effects. There’s a thermometer for its antipyretic effects, and the temperature is so high, it bursts into flames, representing its anti-inflammatory effects.
Okay, in the next coop we also have 2 similar roosters for COX-1 and COX-2, but they’re still alive, because our reversible COX inhibitors are in this coop.
Both of these roosters saw what happened in the first coop, so they took some preventive measures. One is wearing a bulletproof vest for ibuprofen, while the other is reading medical books, because he’s into medicine, or indomethacin.
The book is really hard and it’s making him cry, so let’s give him a box of napkins for naproxen. Finally, as an extra precaution, the bulletproof chicken tore the key to the coop in half, for ketorolac.
For indications, all these medications are used to treat pain, inflammation, and fever, so there’s also a flaming thermometer in this coop.
They can also be used for gout, unlike aspirin, so let’s put a big toe with uric acid crystals roasting above the flame.
For medication-specific indications, a tiny surgeon is trying to repair the key since ketorolac is used after surgeries.
Indomethacin is used to close patent ductus arteriosus, so on the medical book, let’s put a picture of a heart with a duck face inside.
The last coop only has one living two-headed rooster, and this is where we put the reversible selective COX-2 inhibitors.
So let’s have both heads fighting over a stalk of celery, for celecoxib. This pen has the same thermometer with a big gouty toe, since celecoxib has the same indications as the reversible nonselective COX inhibitors.
For side effects, let’s put a bleeding stomach outside each of the coops to represent gastritis and gastric ulcers; the bleeding is most severe in front of the aspirin coop, less severe for the reversible nonselective coop, and there’s almost no bleeding at all for the one in front of the celecoxib coop, since it doesn’t affect COX-1.
Next, let’s put a dying kidney with a tight blood pressure cuff wrapped around its neck in front of all 3 coops, since all NSAIDs affect COX-2 and can cause kidney damage and hypertension.
For cross-hypersensitivity, let’s put “X” shaped boards in front of the door of each coop. On the ground by the door of the aspirin coop, there’s a triangle on the ground for Samter’s triad.
One point is next to the hypersensitivity cross, the next point has an asthma inhaler, and the last point has a big nose with a polyp growing out of its nostril.
Finally, let’s go on top of the Aspirin coop for some of its specific side effects. First, there’s a slice of half eaten rye bread, which represents Reye’s syndrome.
Next, for aspirin overdose, let’s have a young man who represents the early symptoms. He’s wearing headphones for the ototoxicity, and he’s snorting baking soda through a straw for respiratory alkalosis.
Next to him is an older man who represents the later symptoms. This man is in a coma for the CNS toxicities, and next to him are spilled metal cans of acidic soda for metabolic acidosis.
All right, as a quick recap. NSAIDs, or non steroidal anti-inflammatory drugs, work by the inhibition of COX enzymes.

Review15:13–16:06

Irreversible COX inhibitors include aspirin, which works on both COX-1 and COX-2, so it’s nonselective. Reversible COX inhibitors include medications like ibuprofen, which is also non-selective, and celecoxib which is selective for COX-2.
All NSAIDs can be used to treat pain, inflammation, and fever, but only aspirin is used as an antiplatelet medication. Common side effects of NSAIDs include stomach problems, kidney damage, hypertension, and hypersensitivity reactions.
Lastly, aspirin overdose is potentially lethal, and can cause hearing problems, respiratory alkalosis, metabolic acidosis, and coma.

Mind Map16:06–16:18

But wait, there’s more: Here’s a mind map with all of the mnemonics. Go ahead and pause the video so you can test yourself to see what you remember.
Stay tuned for the answers after the credits.