Understanding NSAIDs: Mechanisms, Types, and Effects

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 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 an 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 or pge2

and prostacyclin or 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 depending on how they interact with these enzymes

nsaids are subdivided into two main groups irreversible cox inhibitors like aspirin and reversible cox

inhibitors or non-aspirin nsaids non-aspirin nsaids can be further subdivided into two

groups non-selective cox inhibitors which include common medications like

ibuprofen and selective cox-2 inhibitors like celecoxib

all right now let's start with aspirin also known as acetylsalicylic acid which works by

irreversibly inhibiting both cox-1 and cox-2 aspirin is taken per orally and most of the absorption occurs in the

ilium 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

anti-platelet medication since aspirin irreversibly prevents the platelets from synthesizing new coxone

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 anti-platelet

effect but it does have anti-inflammatory 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 milligrams per day work as an anti-platelet medication

medium doses between 300 and 2 400 milligrams per day work as an antipyretic

and analgesic and high doses over 2 400 milligrams per day work as an anti-inflammatory medication

low doses or baby aspirin in the form of 81 milligram 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 cylindak meloxicam and many others all these medications can be taken per

orally but keturlak ibuprofen and indomethacin are the only nsaids that are also available in

parenteral form just like aspirin these medications inhibit cox-1

and have an anti-platelet 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 anti-platelet 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 endomethacin

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

endomethicin is also used to close patent ductus arteriosus in neonates and premature infants walkie

torilac is used to treat severe acute pain usually after surgery

now moving on to selective cox-2 inhibitors the main medication in this group is

silicoxib celecoxib reversibly inhibits cox-2 so it can treat pain and inflammation

like the other nsaids but since it doesn't affect cox-1 it lacks the anti-platelet effect seen in

aspirin on the other hand it doesn't compete with aspirin for cox-1

like the reversible non-selective cox inhibitors do so it can be combined with aspirin without

decreasing its anti-platelet effect for side effects both aspirin and the non-selective 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 cause the least gi side effects since they don't affect cox-1 at all

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 that 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 bedtime

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 also 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 and said 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 rise syndrome which is

a condition characterized by liver damage and progressive encephalopathy

however aspirin can be used in children to reduce fever in 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 will help you efficiently memorize and retain all of these farm facts so fittingly

let's use a chicken farm full of roosters or for the nsaids which inhibit cox enzymes now in the

first coop there are two dead roosters one with two heads for cox2

and one with a single head for cox1 these roosters are dead to help you remember this coupe contains

the non-reversible cox inhibitors what killed both of these chickens are the two 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 anti-platelet

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 now in the next coop we have two similar roosters for cox 1 and cox 2

but they are 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 preventative measures one is wearing a bulletproof vest for

ibuprofen while the other is reading medical books because he's into medicine

or indomethacin this book is really hard though 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 ketolac for indications all these medications

are used to treat pain inflammation and fever so there's a flaming thermometer in this coop

but they can also be used for gout unlike aspirin so let's put a big toe with the uric

acid crystals roasting above the flame for medication specific

indications a tiny surgeon is trying to repair the key since ketorlak is used after surgeries

endomethacin 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 rooster and it's alive and

it's got two heads so this is where we put the reversible selective cox-2 inhibitors

so let's have both heads fighting over a stalk of celery for silicoxib this coop has the same

thermometer with a big gowdy toe since celecoxib has the same indications as the reversible non-selective 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 coupe less severe for the reversible non-selective coop and there's almost

no bleeding at all for the one in front of the silicoxib coop since that one 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

three cubes since all nsaids affect cox 2 and could 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

for santa'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

rise 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 is a quick recap nsaids or

non-steroidal anti-inflammatory drugs work by the inhibition of cox enzymes irreversible cox inhibitors include

aspirin which works on both cox-1 and cox-2 so it's non-selective reversible cox inhibitors include

medications like ibuprofen which is also non-selective and silicoxid which is selective

for cox 2. all nsaids can be used to treat pain inflammation and fever but only aspirin

is used as an anti-platelet 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 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