in this lecture we're gonna cover
pharmacology of non-steroidal anti-inflammatory drugs known as NSAIDs
as well as pharmacology of prostaglandin analogs but before we do that let's
first discuss what happens during inflammatory response
so following tissue injury or irritation enzyme called phospholipase A2 is
released which converts phospholipids in the cell membrane into arachidonic acid now
arachidonic acid is a substrate for two major enzymes the cyclooxygenase
abbreviated as COX and 5-lipoxygenase abbreviated as 5-LOX in this
lecture we're gonna focus just on the cyclooxygenase pathway now the COX
enzyme exists in different forms two of which are COX-1 and COX-2 the first one
COX-1 isoform is expressed constantly throughout the body and it's primarily
responsible for production of thromboxane and prostaglandins which
stimulate normal body functions such as secretion of protective gastric mucus
regulation of gastric acid promotion of platelet aggregation and maintenance of
renal blood flow now on the other hand COX-2 isoform is not expressed
constantly in most tissues but instead it is induced at sites of inflammation
so unlike COX-1 COX-2-derived prostaglandins mediate mainly
inflammation pain and fever now that we discussed the role of COX enzymes in the
inflammatory response let's talk about mechanism of action of NSAIDs so NSAIDs
act primarily by inhibiting COX enzymes which simply leads to decreased
production of prostaglandins as a result NSAIDs produce anti-inflammatory
antipyretic and analgesic effects now based on their selectivity for COX
enzymes NSAIDs can be divided into three broad categories first selective
COX-1 inhibitors which include Ketorolac Flurbiprofen Ketoprofen Indomethacin and low-dose Aspirin in the second category we have relatively non-selective COX inhibitors which include Naproxen Ibuprofen Piroxicam and Diflunisal and finally in the third category we
have selective COX-2 inhibitors which include Meloxicam Diclofenac
Celecoxib and Etodolac now this relative selectivity for the COX
enzymes explains some of the differences in efficacy and safety of these NSAIDs
so the most common adverse effects of NSAIDs occur in the gastrointestinal
tract this is where COX-1 mediated production of prostaglandin-E2 PGE2
for short and prostacyclin PGI2 for short plays an important role in the
synthesis of protective mucus as well as regulating normal gastric blood flow
this is why inhibition of COX-1 increases risk for GI bleeding and
peptic ulcers agents that are more selective for a COX-1 are associated
with the highest risk now the second major side effect of NSAIDs results from
inhibition of COX-1 mediated production of thromboxane-A2 TXA2
for short as you may remember thromboxane-A2 promotes platelet aggregation
so decrease in its formation results in antiplatelet effect and thus increased
risk of bleeding this effect is particularly evident with the use of
Aspirin which unlike the rest of the NSAIDs irreversibly inhibits COX-1
enzyme in platelets moreover because platelets don't have nucleus they can't
make new enzyme so Aspirin induced antiplatelet effect persist even after
aspirin therapy is stopped as it takes several days for the
new platelets to replace the old ones so again agents with higher selectivity
for COX-1 enzyme are also associated with prolonged bleeding time now let's
discuss the third major adverse effect of NSAIDs which results from their
actions on the kidney so renal prostaglandins specifically E2 and I2
types cause dilation of the renal afferent arteriole which is important
for maintaining glomerular filtration rate that being said under normal
conditions these prostaglandins have only minimal effect on renal perfusion
however when kidney function becomes compromised for example
due to heart failure or old age the production of prostaglandins becomes a
significant factor in preservation of the renal blood flow so because NSAIDs
decrease production of renal prostaglandins they also may increase
the risk of kidney injury in susceptible patients now the last major adverse
effect of NSAIDs that I wanted to discuss results from their actions on
cardiovascular system so while agents such as Aspirin with high COX-1
selectivity can have protective cardiovascular effect due to the
antiplatelet properties agents with high COX-2 selectivity can have the opposite
effect in order to understand where this adverse effect comes from let's take a
look at the blood vessel supplying blood to the heart so under normal conditions
we have a balanced effect between prostacyclin and thromboxane-A2 now
prostacyclin is produced mainly by COX-2 in the
endothelium and it's responsible for vasodilation and inhibition of platelet
activation on the other hand thromboxane-A2 is produced mainly by COX-1 in
platelets and it's responsible for vasoconstriction and promotion of
platelet aggregation so now the problem arises when selective inhibition of COX-2 tips the balance in favor of thromboxane-A2 formation this makes
vasoconstriction and platelet aggregation more likely to occur this in
turn leads to increased risk of cardiovascular events including
myocardial infarction and stroke now that we discuss NSAIDs let's talk a
little bit more about prostaglandins so even though prostaglandins can produce
many unwanted effects such as inflammation they're also responsible
for many beneficial effects in order to harness those beneficial effects
scientists developed prostaglandin analogs which simply mimic our
endogenous prostaglandins now prostaglandins exert their effects by
interacting with specific G-protein coupled prostaglandin receptor of which
there are at least nine known subtypes the effects of particular prostaglandin
may vary widely depending on the tissue and expressed receptors so now let's
discuss some of the commonly used prostaglandin analogs
starting with analogs of prostaglandin-E1 example of agents that belong to this
group are Alprostadil Lubiprostone and Misoprostol although all these agents
are derived from prostaglandin-E1 they were designed for different therapeutic
purposes so Alprostadil has two main therapeutic uses first is erectile
dysfunction when Alprostadil is applied into the urethra
it acts via direct stimulation of cAMP pathway to decrease intracellular
calcium levels allowing for relaxation of trabecular smooth muscle and dilation
of cavernosal arteries this ultimately leads to
improved erectile function secondly Alprostadil is used in neonates with
congenital heart defects to temporarily maintain the patency of ductus
arteriosus so for those of you who need a refresher ductus arteriosus is a
blood vessel found in babies before birth that allows blood to bypass the
pathway to the lungs although this blood vessel typically closes shortly after
birth keeping it open in certain babies with heart defects may improve blood
flow and oxygenation so infusion of Alprostadil relaxes the ductus
arteriosus and supports its patency until surgery can be performed now let's
move on to the next prostaglandin-E1 analog that is Lubiprostone so
Lubiprostone is used in the treatment of chronic constipation it works by
activating type-2 chloride channels in epithelial cells lining the intestine by
stimulating these channels Lubiprostone promotes secretion of chloride followed
by passive secretion of sodium and water which increase the liquidity of the
intestinal contents this secretion also stimulates intestinal smooth muscle
contractions which facilitate the passage of stool now let's move on to
the next prostaglandin-E1 analog that is Misoprostol so Misoprostol is another
prostaglandin-E1 analog and it is used to treat and prevent stomach ulcers
particularly in patients taking NSAIDs it can also be used to
induce labor Misoprostol works by binding to the prostaglandin receptor on
the gastric parietal cell and causing decrease in intracellular cAMP leading to
decreased activity of proton pump and thus modest inhibition of acid secretion
furthermore Misoprostol protects the stomach lining by increasing bicarbonate
and mucus production lastly by interacting with prostaglandin receptors
in the uterus Misoprostol causes softening of cervix and uterine
contractions leading to the expulsion of the uterine contents now let's move on to
prostaglandin-F2alpha analogs example of agents that belong to this
group are Bimatoprost Latanoprost and Travoprost these agents are used
opthalmically for treatment of open-angle glaucoma they work by increasing the
outflow of aqueous fluid from the eye and thus lowering intraocular pressure
although Latanoprost and Travoprost accomplish that by interacting with
prostaglandin-F receptors located throughout the eye Bimatoprost is
thought to have a different mechanism of action which is currently unknown
furthermore among the unique side effects of Bimatoprost is
elongation and darkening of the eyelashes which makes Bimatoprost
useful in treatment of eyelash hypotrichosis now let's move on to the
last group of analogs that is prostacyclin analogs example of agents that
belong to this group are Iloprost and Treprostinil these agents are used to
treat pulmonary arterial hypertension they work by increasing production of
cAMP which leads to decreased levels of intracellular calcium in pulmonary
vascular smooth muscle cells ultimately causing vasodilation this results in
significant reduction in pulmonary vascular resistance and enhanced cardiac
index and with that I wanted to thank you for watching I hope you enjoyed this
video and as always stay tuned for more