NSAIDS - Non-steroidal anti-inflammatory drugs. Flashcards
What are Eicosanoids?
Local hormones derived upon request from arachidonic acid.
What is Arachidonic acid?
a constituent
of the membrane phospholipids.
How is AA released?
AA is released by the direct action of phospholipase A2 . AA is metabolized to give rise to eicosanoids:
- Prostanoids (prostaglandins and thromboxanes)
- Leucotrienes
What are prostanoids?
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
What are the two forms of COX?
There are two forms of COX:
◦ COX-1: constitutive enzyme, involved in tissue homeostasis
◦ COX-2: induced in inflammatory cells by an inflammatory stimulus
What is Prostacyclin (PGl2)?
Prostanoid
predominantly
from vascular endothelium
◦ Vasodilation
◦ Inhibition of platelet aggregation
◦ Sensitization of nerve pain terminals
what is thromboxane A2 (TXA2)?
Prostanoid
predominantly from platelets
◦ Platelet aggregation
◦ Vasoconstriction
What is Prostaglandin E1
(PGE1) и E2 (PGE2)?
Prostanoid
◦ Mediators of inflammation and fever
◦ Inhibition of gastric acid secretion
◦ Contraction of pregnant uterus and GI smooth muscle
What is Prostaglandin F2α
(PGF2α)?
◦ Contraction of the uterus
◦ Contraction of vascular and non-vascular smooth muscle
What are the clinical uses of prostaglandins in obstetrics?
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)
What are the clinical uses of prostaglandins in the gastrointestinal tract?
◦ To prevent peptic ulcers in patients taking NSAIDs: Misoprostol (PGE1)
What are the clinical uses of prostaglandins in ophthalmology?
◦ Open-angle glaucoma: latanoprost, etc. as eye drops
Which prostanoids are used in cardiology?
◦ Аlprostadil (PGE1)
◦ Iloprost (PGI2)
What are leukotrienes?
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)
What does LTB4 do?
LTB4 acting on specific receptors:
◦ Causes adherence, chemotaxis and activation of polymorphs and
monocytes
◦ Is important mediator in all types of inflammation
What do the cysteinyl-LTs act on and what do they cause?
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)
How are the NSAIDs classified?
I. Non-selective COX-inhibitors
II. Relatively selective COX-2 inhibitors
III. Selective COX-2 inhibitors (coxibs)
How are the Non-selective COX-inhibitors classified?
- Salicylic acid derivatives
- Acetic acid derivatives
- Enolic acid derivatives (oxicams)
- Propionic acid derivatives
What is the PK of NSAIDs?
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)
What are the PDs of NSAIDs?
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
What are the adverse reactions of NSAIDs?
◦ 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.
What are the clinical uses of NSAIDs?
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
What are selective COX-2 inhibitors?
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).
