Physiology & Pharmacology of Eicosanoids

Question 1

Define eicosanoid

Answer 1

oxygenation products of polyunsaturated long-chain fatty acids

Question 2

Describe the general process involved in the synthesis of eicosanoids

Answer 2

• AA –> COX –> peroxidase –> PGH2 –> prostaglandins
• AA –> 5-lipoxygenase –> 5-HPETE –> LTB4 –> leukotrienes
• AA –> cytochrome 450 –> HETE
• AA –> 2 cyclooxygenases –> prostaglandin isomerases –> thromboxane

Question 3

Describe in general the receptors that can bind eicosanoids, the family they belong to, and the signal transduction mechanisms they are coupled to

Answer 3

GPCRs

Question 4

Compare and contrast the responses evoked by eicosanoids in various organs of the body

Answer 4

Constitutive COX1: GI tract, CNS fever, peripheral pain, platelets , endothelium, kidney
Inducible COX2: peripheral inflammation, uterus, GI cancers
Constitutive COX2: renal sodium, endothelium, kidney, CNS pain, CNS fever

Question 5

Compare and contrast the mechanism of action of drugs that modify synthesis and responses evoked by eicosanoids

Answer 5

Non-selective COX Inhibitors: inhibit both thromboxane and prostacyclin formation; net effect on coronary thrombosis is variable
Selective COX2 Inhibitors: inhibit prostacyclin formation; results in platelet aggregation and vasoconstriction (coronary artery thrombosis) and gastric mucin formation

Question 6

What are the adverse effects of NSAIDs?

Answer 6

• hypertension: increased arteriole vascular resistance, reduced Na+ excretion in urine, increased water reabsorption from collecting duct
• NSAIDs Induced Renal Failure: attenuation of afferent arteriole dilation and renal artery dilation, reduced GFR
• CNS (tinnitus, dizziness), cardiovascular renal (Na+ and H2O retention, hypertension, edema), GI (abdominal bleeding dyspepsia, ulcer formation), Histological (rare), Hepatic (elevated liver enzymes), pulmonary (asthma), skin (pruritis), renal (renal insufficiency)

Question 7

What are the adverse effects of 5-lipoxygenase inhibitors?

Answer 7

.

Question 8

What are the adverse effects of leukotriene receptor antagonists?

Answer 8

Cardiovascular system: reduces myocardial contractility and coronary blood flow to depress CO
Airways: bronchoconstrictor, increased permeability, plasma exudation, and mucus secretion

Question 9

What is the most abundant eicosanoid precursor?

Answer 9

arachidonic acid

Question 10

Why do is there great therapeutic potential in affecting eicosanoids?

Answer 10

due to the availability and potential of specific receptor antagonist and enzyme inhibitors

Question 11

What is involved in releasing AA from the membrane phospholipids?

Answer 11

cPLA2: translocates from the membrane to release AA (Ca+ dependent)
iPLA2: liberates AA that recycles back to membrane (little eicosanoids produced)
sPLA2: liberates AA when there’s a sustained production of eicosanoids

Question 12

What are the major classes of Eicosanoids?

Answer 12

prostaglandins, leukotrienes, thromboxanes

Question 13

What are NSAIDs?

Answer 13

non-steroidal anti-inflammatory drugs

-inhibit COX enzymes

Question 14

Examples of NSAIDs

Answer 14

Aspirin (irreversible)
Naproxen, ibuprofen (reversible)
Indomethacin, Diclofenac, Sulindac (reversible)
Celecoxib - selective COX2 inhibitor (only one)
Acetaminophen – has anti-pyretic and analgesic properties but no anti-inflammatory properties

Question 15

What is antipyresis?

Answer 15

decreases body temperature from fever

Question 16

What are the pharmacological actions of NSAIDs?

Answer 16

antipyresis: alter elevated thermostatic set point; increase loss of heat by vasodilation and increased sweating
analgesia: decreasing PGs
anti-inflammatory action: decrease levels of PGs