Eicosanoids

Question 1

Eicosanoids

Answer 1

Prostaglandins, Thromboxane, Leukotrienes

• 20 carbon structure
• Arachidonic acid ⇒ most common precursor in humans

Question 2

Leukotrienes

Answer 2

• Made by inflammatory cells upon ⊕ of PLA₂ and Lipoxygenase (5-LOX)
• Leukotriene C4 and D4 (LTC₄ and LTD₄)
  
  • Slow-reacting substance of anaphylaxis (SRS-A)
    
    • Airway inflammation and edema
    • Bronchoconstriction
    • Secretion of thick mucus
  • More potent than histamine but slower onset and longer duration

Question 3

Zarfirlukast and Montelukast

Answer 3

Leukotriene Antagonists

• Alternatives for long-term control of mild to moderate asthma and seasonal allergies
  
  • ↓ Incidence of attacks
  • Not used for acute treatment
    
    • Max effects can take weeks
• Zarfirlukast ⇒ ⊗ CYP2C9 and CYP3A4
  
  • Drug interactions
• Montelukast ⇒ does not interact with CYP450 system

Question 4

Zilueton (Zyflo)

Answer 4

5-Lipoxygenase Inhibitor

• Alternative for long-term control of mild to moderate asthma
• Must be taken 4x/day ⇒ compliance issues
• ⊗ CYP1A2 and CYP3A4 ⇒ drug interactions
• Adverse effects:
  
  • Flu-like symptoms
  • GI upset
  • Elevation of liver enzymes

Question 5

Prostaglandins

Overview

Answer 5

• Production stimulated by ⊕ of PLA2
• Trauma or specific stimuli
• Act as autocrine and paracrine mediators
• Short half-life and act rapidly near site of synthesis ⇒ autacoids
• Share a common prostanoid structure
• Produced by most cells
• Relative abundance of each product depends on enzyme pattern

Question 6

Prostaglandins

Platelet Effects

Answer 6

• Vessel injury ⇒ platelet binds to endothelium ⇒ activation ⇒ Thromboxane A₂ (TXA₂) synthesis by platelets
  
  • COX₁ is the major enzyme responsible
  • TXA₂ ⇒ platelet aggregation & vasoconstriction
• Endothelium releases Prostacyclin I₂ (PGI₂)
  
  • COX₂ is the major enzyme responsible
  • PGI₂ ⇒ ⊗ platelet aggregation & vasodilation
• ω-3 fatty acids found in fish oils ⇒ synthesis of thromboxane A₃ (TXA₃)
  
  • Weaker form ⇒ ↓ in strokes and heart attacks

Question 7

Prostaglandins

Renal Effects

Answer 7

• Kidney makes PGE₂ and PGI₂
  
  • Vasodilation of afferent arteriole
    
    • Esp. in pts w/ renal insufficiency and the elderly
    • Maintains renal blood flow and glomerular filtration
  • ↑ sodium and water excretion
• COX inhibitors ⇒ ⊗ prostaglandin synthesis
  
  • Disrupt RBF balance
  • Can cause HTN or kidney failure

Question 8

Prostaglandins

Cardiac Effects

Answer 8

• PGE₂ and PGI₂ maintain patency of ductus arteriosus (PDA)
  
  • Usually closes shortly after birth
• In some cases, esp. premature births, it remains open
  
  • Indomethacin or ibuprofen ⇒ COX inhibitors used to close a PDA
• Need to maintain PDA patency in some cases of congenital heart problems pending surgery
  
  • Done using Alprostadil ⇒ PGE₁ analogue

Question 9

Prostaglandins

Pulmonary Effects

Answer 9

PGE₂ and PGI₂ ⇒ arterial vasodilation in the lung ⇒ ↑ pulmonary blood flow

Question 10

Epoprostenol

(Flolan)

Answer 10

PGI₂ analogue

• Used to treat primary and secondary pulmonary HTN
• Adverse effects:
  
  • Hypotension
  • Flushing
  • Headache
  • Nausea and diarrhea
• Other possible treatments are:
  
  • Calcium channel blocker (nifedipine)
  • Supplemental oxygen
  • Bosentan (endothelin antagonist)
  • Sildenafil (phosphodiesterase inhibitor)

Question 11

Alprostadil

Answer 11

PGE₁ analogue

• Causes penile vasodilation
• Given by injection to treat erectile dysfunction

Question 12

Trimix

Answer 12

Alprostadil (PGE1 analogue) + Papaverine (? phosphodiesterase inhibitor) + Phentolamine (α-blocker)

Given via injection for erectile dysfunction.

Question 13

Prostaglandins

Female Reproductive Effects

Question 14

Prostaglandins

Glaucoma Therapy

Question 15

Dinoprostone

Answer 15

PGE₂ analgoue

Given as a vaginal gel or insert

• Induces labor by:
  
  • ↑ proteoglycan content & ∆ biophysical properties of collagen ⇒ cervix softening
  • ⊕ Uterine contraction
• May be used as an abortifacient
• May cause nausea, vomiting, or diarrhea

Question 16

Carboprost

Answer 16

PGF_2a analog

• Used for 2^nd trimester abortions
  
  • Given via intramuscular injection
• May cause vomiting and diarrhea

Question 17

Misoprostol

Answer 17

PGE₁ analog

Used in combo w/ mifepristone to produce early abortion

Mifepristone terminates pregnancy by blocking progesterone receptors

Misoprostol functions to expel the fetus

May cause cramping pain and diarrhea

Question 18

Latanoprost

Answer 18

• Long-lasting PGF₂ derivative
• ↑ Outflow of aqueous humor through uveoscleral pathway ⇒ ↓ IOP
• Used to treat glaucoma
• Side effects:
  
  • ↑ Eyelash length
  • May change iris color