L18 & 19 - NSAIDs Flashcards
Explain how arachidonic acid is released from the membranes
Released from membrane phospholipids by phospholipase A2 (PLA-2)
What is the physiological effect of PGE-2 on blood vessels?
dilation
What is the physiological effect of PGF-2a on blood vessels?
constriction
What is the physiological effect of PGI-2 on blood vessels?
dilation
What is the physiological effect of TXA-2 on blood vessels?
constriction
What is the physiological effect of PGI-1 on platelets?
inhibition of aggregation
What is the physiological effect of TXA-2 on platelets?
promotion of aggregation
What is the physiological effect of PGE-2 on bronchi?
dilation
What is the physiological effect of PGF-2a on bronchi?
constriction
What is the physiological effect of PGE-2 on the uterus?
oxytocic dilation
What is the physiological effect of PGF-2a on the uterus?
oxytocic constriction
List the end products of the cyclooxygenase pathways
Prostaglandins (“PG”)
Thromboxanes (“TX”)
List the end products of the lipoxygenase pathways
Leukotrienes
Also - HPETEs, Lipoxins
List the effects of COX-1 inhibition
GI effects
- Stomach irritation & ulceration
- Blockade of platelet aggregation
- Inhibition of uterine motility
- Inhibition of PG-mediated renal function
- Hypersensitivity reactions
List the effects of COX-2 inhibition
- Pain relief
- Elevated blood pressure
- Accelerated atherogenesis
Describe Alprostadil
a therapeutic prostaglandin
- PGE-1
- Relaxes smooth muscles and expand blood vessels
- Used for erectile dysfunction by injection or as a suppository
Describe misoprostol
a therapeutic prostaglandin
- PGE-1 derivative
- Cytoprotective
- Prevents peptic ulcer, terminates early pregnancy in combination with mifepristone
Describe latanoprost
a therapeutic prostaglandin
- topically active PGF-2a derivative (prodrug)
- constricts blood vessels
- used in ophthalmology to treat high pressure inside eye (ex. glaucoma)
Describe prostacyclin
a therapeutic prostaglandin
- PGI-2
- Powerful vasodilator, inhibitor of platelet aggregation
- Used to treat pulmonary arterial hypertension by IV injection or inhalation
(shouldn’t be used with anticoagulants)
List the pharmacological activities of NSAIDs
Anti-inflammatory
Analgesic → pain killing
Antipyretic → fever suppressant
Explain the mechanism of action of NSAIDs
Inhibition of prostaglandin endoperoxide H synthase (PGHS or COX), which catalyzes the formation of prostaglandins
(Many NSAIDs inhibit both COX-1 and COX-2)
Explain the mechanism of gastric bleeding caused by NSAIDs
- Primary insult → acidity of many NSAIDs
- Secondary insult → Inhibition of synthesis of cytoprotective prostaglandins (PGEs) in gastric mucosa
- There is also an inhibition of platelet aggregation → causes increased tendency of bleeding
Explain the mechanism of the inhibition of blood coagulation by aspirin
Irreversible inhibition of platelet COX-1 and the consequent reduced formation of thromboxane
What is Reye’s syndrome?
- A rare, acute, life-threatening condition characterized by vomiting, delirium, and coma
- Brain damage is common in survivors
What is one of the causes of Reye’s syndrome?
giving salicylates (aspirin) to children who have had the chicken pox or flu
Who should aspirin NOT be given to?
anyone under the age of 12 who has a fever
Explain the main cause of drug interactions of NSAIDs
NSAIDs compete with other drugs for serum albumin binding sites (ex oral anticoagulants)
List the classes of NSAIDs
Salicylates
Arylacetic acids
Arylpropionic acids
Non-carboxylate NSAIDs
COX-2 selective NSAIDs
Explain the role of α-methyl group in the structure-activity relationship of arylpropionic acids
The α-Methyl group enhances it activity and reduces many side effects
Describe the difference in the mechanism of action of acetaminophen from that of NSAIDs
It does not inhibit arachidonic acid binding to PGHS
What is the mechanism of action of acetaminophen?
- Prevents PGH synthase activity by scavenging for Peroxynitrite, the major oxidant for PGH synthase activity in the CNS
- In inflammation, high concentrations of peroxides are present, and acetaminophen scavenging is overwhelmed
List NSAIDs that are prodrugs
Sulindac
Nabumetone (non-acidic)
How is Sulindac converted to its active metabolite?
the sulfoxide group is reduced to the active sulfide intermediate in the circulatory system
How is Nabumetone converted to its active metabolite?
Metabolized rapidly to 6-methoxynaphthalene-acetic acid (6-MNA), which is an effective inhibitor of COX
Explain the structural basis of selective COX-2 inhibitors
- Selective COX-2 inhibitors exploit the larger NSAID binding site in COX-2 (valine) with larger and relatively rigid substituents
- Prevented from binding to COX-1 because of the smaller isoleucine binding site
Describe the mechanism of elevated blood pressure caused by selective COX-2 inhibitors
- Constitutive expression of COX-2 in endothelium is critical for production of PGI-2 (prostacyclin)
- High PGI-2 production → dilation of blood vessels & inhibited aggregation of platelets
Describe the mechanism of accelerated atherogenesis caused by selective COX-2 inhibitors
- Selective COX-2 inhibitors do not affect the production of TXA-2 by COX-1; heightened thrombotic response on the rupture of atherosclerotic plaque
- Lower levers of TXA-2 → no constriction to combat dilation, no aggregation being promoted
List the side effects of selective COX-2 inhibitors
elevated blood pressure
accelerated atherogenesis
List examples salicylates
Salicylic acid
Aspirin
Salsalate (Disalcid)
Diflunisal (Dolobid)
List examples of arylacetic acids
Indomethacin (Indocin, Tivorbex)
Sulindac (Clinoril)
Etodolac (Lodine)
Diclofenac (Cataflam, Voltaren)
List examples of non-carboxylates
Nabumetone (Relafen)
Meloxicam (Mobic, Vivlodex)
List examples of COX-2 selective inhibitors
Celecoxib (Celebrex)
List examples of eicosanoid drugs
Alprostadil (Edex)
Misoprostol (Cytotec)
Latanoprost (Xalatan, Monopost)
Prostacyclin (Epoprostenol)
