NSAIDS - Non-steroidal anti-inflammatory drugs.

Question 1

What are Eicosanoids?

Answer 1

Local hormones derived upon request from arachidonic acid.

Question 2

What is Arachidonic acid?

Answer 2

a constituent

of the membrane phospholipids.

Question 3

How is AA released?

Answer 3

AA is released by the direct action of
phospholipase A2
.
AA is metabolized to give rise to
eicosanoids:

• Prostanoids (prostaglandins and thromboxanes)
• Leucotrienes

Question 4

What are prostanoids?

Answer 4

Prostanoids (prostaglandins and
thromboxanes)

They are produced by cyclooxygenase (COX).

There are two forms of COX:
◦ COX-1: constitutive enzyme, involved in tissue homeostasis
◦ COX-2: induced in inflammatory cells by inflammatory stimulus

Question 5

What are the two forms of COX?

Answer 5

There are two forms of COX:
◦ COX-1: constitutive enzyme, involved in tissue homeostasis
◦ COX-2: induced in inflammatory cells by an inflammatory stimulus

Question 6

What is Prostacyclin (PGl2)?

Answer 6

Prostanoid

predominantly
from vascular endothelium

◦ Vasodilation
◦ Inhibition of platelet aggregation
◦ Sensitization of nerve pain terminals

Question 7

what is thromboxane A2 (TXA2)?

Answer 7

Prostanoid

predominantly from platelets
◦ Platelet aggregation
◦ Vasoconstriction

Question 8

What is Prostaglandin E1

(PGE1) и E2 (PGE2)?

Answer 8

Prostanoid

◦ Mediators of inflammation and fever
◦ Inhibition of gastric acid secretion
◦ Contraction of pregnant uterus and GI smooth muscle

Question 9

What is Prostaglandin F2α

(PGF2α)?

Answer 9

◦ Contraction of the uterus

◦ Contraction of vascular and non-vascular smooth muscle

Question 10

What are the clinical uses of prostaglandins in obstetrics?

Answer 10

In obstetrics

◦ For induction of labor: Dinoprostone (PGE2) (vaginally in the form of a gel or controlled-release formulation)
◦ For termination of pregnancy: Carboprost (PgF2α)

Question 11

What are the clinical uses of prostaglandins in the gastrointestinal tract?

Answer 11

◦ To prevent peptic ulcers in patients taking NSAIDs: Misoprostol (PGE1)

Question 12

What are the clinical uses of prostaglandins in ophthalmology?

Answer 12

◦ Open-angle glaucoma: latanoprost, etc. as eye drops

Question 13

Which prostanoids are used in cardiology?

Answer 13

◦ Аlprostadil (PGE1)

◦ Iloprost (PGI2)

Question 14

What are leukotrienes?

Answer 14

5-lipoxygenase acts on arachidonate to give 5-hydroxyperoxyeicosatetraenoic acid (5-HPETE),
which is converted to leucotriene
LTA4

LTA4
in turn can be converted to:
◦ LTB4
◦ Series of cysteinyl-LTs (LTC4, LTD4, LTE4)

Question 15

What does LTB4 do?

Answer 15

LTB4 acting on specific receptors:

◦ Causes adherence, chemotaxis and activation of polymorphs and
monocytes
◦ Is important mediator in all types of inflammation

Question 16

What do the cysteinyl-LTs act on and what do they cause?

Answer 16

CysLT1 and CysLT2
receptors

◦ Cause contraction of the bronchial muscle
◦ Are of particular importance in asthma

Anti-leucotriene drugs:
◦ Cys-LT1
receptor antagonists: Мontelucast (used in asthma)

Question 17

How are the NSAIDs classified?

Answer 17

I. Non-selective COX-inhibitors

II. Relatively selective COX-2 inhibitors

III. Selective COX-2 inhibitors (coxibs)

Question 18

How are the Non-selective COX-inhibitors classified?

Answer 18

1. Salicylic acid derivatives
2. Acetic acid derivatives
3. Enolic acid derivatives (oxicams)
4. Propionic acid derivatives

Question 19

What is the PK of NSAIDs?

Answer 19

NSAIDs are weak acids:
• Well absorbed orally
Highly bound (98%) to plasma
proteins

• They can displace other drugs
Metabolism – CYP, conjugation
reactions

Excretion:
• Predominantly renal
• In the bile (enterohepatic circulation)

Question 20

What are the PDs of NSAIDs?

Answer 20

Anti-inflammatory effect: mainly in the acute phase of
inflammation, due to inhibiting PG-dependent
symptoms:
◦ Vasodilation
◦ Edema
◦ Pain

Antipyretic effect: action in the hypothalamus

Analgesic effect: NSAIDs reduce pain in inflammation
owing to decreased sensitization of nociceptive nerve terminals to substances such as bradykinin or
serotonin

Question 21

What are the adverse reactions of NSAIDs?

Answer 21

◦ Gastrointestinal: Abdominal pain, nausea,
vomiting, and rarely, ulcers or bleeding;

◦ Renal: Renal insufficiency, renal failure,
hyperkalemia, and proteinuria;

◦ Cardiovascular: Fluid retention,
hypertension, edema, and rarely, myocardial
infarction and congestive heart failure (CHF);

◦ Hepatic: Abnormal liver function test results
and rare liver failure (especially
Nimesulide);

◦ Hematologic: Rare thrombocytopenia,
neutropenia, or even aplastic anemia;

◦ Pulmonary: Asthma (aspirin-sensitive
asthma);

◦ Skin: Rashes, pruritus;

◦ Central nervous system: Headaches,
tinnitus, dizziness.

Question 22

What are the clinical uses of NSAIDs?

Answer 22

As analgesics (headache, dysmenorrhea, pain in the
spine, bone metastases, postoperative pain)

As anti-inflammatory drugs in rheumatoid diseases
(acute gout, osteoarthritis, ankylosing spondylitis,
rheumatoid arthritis, inflammation of soft tissues)

As antipyretics: ASA, Ibuprofen
◦ ASA be avoided in children with viral infections (Reye
syndrome)

ASA (low doses: 75-100 mg) – antiplatelet effect –
for prevention and treatment of myocardial
infarction

Question 23

What are selective COX-2 inhibitors?

Answer 23

As anti-inflammatory drugs – equally effective
with the non-selective COX-inhibitors

The gastrointestinal ADRs are reduced, but not
the renal.

They have no effect on platelets but inhibit the
synthesis of PGI2
, resulting in an increased incidence
of acute thrombotic events (AMI, stroke).