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