Pharmacology – NSAIDs & PROSTAGLANDIN ANALOGS (MADE EASY)

Pharmacology – NSAIDs & PROSTAGLANDIN ANALOGS (MADE EASY)

July 20, 2019 88 By William Morgan


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