NSAIDS Flashcards
What’s an inflammation and why does it happen
Inflammation: is a normal, protective response to tissue injury.
It is caused by:
physical trauma, noxious chemicals, or microbiologic agents.
▪ Why Inflammation occurs in our body:
1) To inactivate or destroy invading organisms
2) Remove irritants
3) Set the stage for tissue repair
INAPPROPRIATE activation of the immune system can result in
inflammation, leading to immune-mediated diseases such as
rheumatoid arthritis (RA).
What is RA
white blood cells (WBCs) view the synovium
(tissue that nourishes cartilage and bone) as non-self and initiate an
inflammatory attack.
✓ WBC activation leads to stimulation of T lymphocytes, which activate
monocytes and macrophages
These cells secrete
proinflammatory cytokines,
including tumour necrosis factor
(TNF)-α and interleukin (IL)-1,
into the synovial cavity.
In addition to T-lymphocyte activation, B lymphocytes are also involved
and produce RF (Rheumatiod factor an inflammatory marker) and other
autoantibodies with the purpose of maintaining inflammation.
What does the cytrokines cause
1) ↑ cellular infiltration into the endothelium due to release of
histamines, kinins, and vasodilatory PGs
2) ↑ production of C-reactive protein by hepatocytes
3) ↑ production and release of proteolytic enzymes by chondrocytes,
leading to degradation of cartilage and joint space narrowing
4) ↑ osteoclast activity (osteoclasts regulate bone breakdown), resulting in
focal bone erosions and bone demineralization around joints
5) systemic manifestations in certain organs such as the heart
What is the pharmacotherapy of RA
anti-inflammatory and/or
✓ immunosuppressive agents that modulate/reduce the
inflammatory process, Disease-Modifying Antirheumatic
Drugs (DMRDs)
What is the role of prostaglandins as local mediators
PGs and related compounds are produced in minute quantities by
virtually all tissues.
✓ They generally act locally on the tissues in which they are synthesized,
and they are rapidly metabolized to inactive products at their sites of
action → PGs do not circulate in the blood in significant
concentrations.
✓ TXs and LTs are related lipids that are synthesized from the same
precursors as the PGs.
What is the precursor of prostaglandins
Arachidonic acid (AA) is present as a component of the phospholipids of cell membranes.
Free AA is released from tissue phospholipids by the action of
phospholipase A2 (PLA-2) via a process controlled by hormones and
other stimuli.
What is the cyclooxygenase pathway for making prostaglandins
✓ Cyclooxygenase-1 (COX-1) is responsible for the physiologic production
of prostanoids
✓ COX-1 is a constitutive enzyme that regulates normal cellular processes,
such as:
✓ gastric cytoprotection,
✓ vascular homeostasis,
✓ platelet aggregation, and
✓ reproductive and
✓ kidney functions.
✓ cyclooxygenase-2 (COX-2) causes the elevated production of
prostanoids that occurs in sites of chronic disease and inflammation
✓ COX-2 is constitutively expressed in tissues such as the brain, kidney,
and bone.
✓ Its expression at other sites is increased during states of chronic
inflammation.
✓ Differences in binding site shape have permitted the development of
selective COX-2 inhibitors (Figure 36.2).
✓ Another distinguishing characteristic of COX-2 is that its expression is
induced by inflammatory mediators like TNF-α and IL-1
✓ but can also be pharmacologically inhibited by glucocorticoids
, which may contribute to the significant anti-inflammatory effects
of these drugs
Alternatively, several lipoxygenases can act on AA to form LTs (Antileukotriene drugs, such as zileuton, zafirlukast, and montelukast,
are treatment options for asthma.
What are the actions of prostaglandins
✓ Many of the actions of PGs are mediated by their binding to a wide
variety of distinct cell membrane receptors that operate via G-coupled
proteins.
✓ PGs and their metabolites, produced endogenously in tissues, act as
local signals that fine-tune the response of a specific cell type.
✓ Their functions vary widely, depending on the tissue and the specific
enzymes within the pathway that are available at that particular site
✓ For example, the release of thromboxane A2 (TXA2) from platelets
during tissue injury triggers the recruitment of new platelets for
aggregation, as well as local vasoconstriction.
✓ However, prostacyclin (PGI2), produced by endothelial cells, has
opposite effects, inhibiting platelet aggregation and producing
vasodilation.
✓ The net effect on platelets and blood vessels depends on the balance of
these two prostanoids.
What is the therapeutic use for PG
✓ PGs have a major role in modulating pain, inflammation, and fever.
✓ They also control many physiological functions, such as acid secretion
and mucus production in GIT, uterine contractions, and renal blood
flow.
✓ PGs are also among the chemical mediators that are released in allergic
and inflammatory processes.
✓ This leads to many therapeutic applications for prostaglandins
What is Alprostadil PGE1 ANALOGUE
✓ It is a PGE1
analogue that is naturally (seminal vesicles, cavernous
tissues, placenta, ductus arteriosus of the fetus).
✓ It is used to treat erectile dysfunction
✓ PGE1 maintains the patency of the ductus arteriosus during pregnancy.
The ductus closes soon after delivery to allow normal blood circulation
between the lungs and the heart.
✓ Alprostadil keeps the ductus arteriosus open in neonates with
congenital heart conditions until surgery is possible (Infusion of the
drug maintains the ductus open as it naturally occurs during pregnancy,
allowing time until surgical correction is possible)
What is lubiprostone PGE1 ANALOGUE
✓ It is a PGE1 derivative
✓ It is indicated for the treatment of:
chronic idiopathic constipation, opioid-induced constipation, and irritable
bowel syndrome with constipation.
✓ MOA: It stimulates Chloride-channels in the luminal cells of the intestinal
epithelium, thereby ↑ intestinal fluid secretion.
✓ SEs: Nausea and diarrhea
✓ Nausea can be decreased if taken with food.
What are misoprostol PGE1 ANALOGUE
✓ It is used to protect the mucosal lining of the stomach during chronic
NSAID treatment. ( ↓ HCl secretion, has a GI cytoprotective effect).
✓ There is a combination product containing diclofenac and misoprostol.
✓ Misoprostol is also used off-label* in obstetric settings for:
✓ labor induction, since it ↑ uterine contractions.
✓ Misoprostol has the potential risk to induce abortion in pregnant
women. Therefore, the drug is CI during pregnancy.
✓ Its use is limited by common SE: diarrhea and abdominal pain.
*Off-label: the use of drug to treat a condition for which it has not
received approval by a regulatory agency.
What is Dinoprostone PGE2 Analogue
• Labor induction
• An abortifacient
• Route of administration: via the vagina ( as a gel or a
removable insert)
• Actions:
• Relaxation of cervical smooth muscles
• Induction of uterine contractions
• Common A/E: fever, chills, N/V, diarrhea and headache